Infectious Diseases

A new virus has been associated with febrile illness in China in patients with histories of tick bites. The data on the discovery, isolation, and characterization of the virus were reported in the New England Journal of Medicine.

The segmented RNA virus now known as Alongshan virus (ALSV) “belongs to the unclassified jingmenvirus group in the family Flaviviridae, which includes the genera flavivirus, pestivirus, hepacivirus, and pegivirus,” wrote Ze-Dong Wang, PhD, of Foshan (China) University, and colleagues.

The index patient with ALSV was a 42-year-old female farmer from the town of Alongshan, China, who presented to a regional hospital in April 2017 with fever, headache, and a history of tick bites. The initial clinical features were similar to those seen in tickborne diseases, but a blood sample showed no RNA or antibodies for tickborne encephalitis virus. Investigators obtained a blood specimen from the index patient 4 days after the onset of illness. After culturing the sample, the investigators extracted the viral RNA genome and sequenced it.

Sequence analysis found that the new pathogen was related to segmented viruses in the jingmenvirus group of the family Flaviviridae; however, “comparison of the amino acids further confirmed that ALSV is genetically distinct from other jingmenviruses,” the investigators said.

The investigators identified 374 patients who presented to the hospital with fever, headache, and a history of tick bites during May 2017–September 2017; 86 patients had confirmed ALSV infections via nested reverse-transcription polymerase chain reaction testing. Of these, 63 were men and 84 were farmers or forestry workers. Although ticks were common in the patients’ environments, no other evidence of tickborne diseases was noted. The patients ranged in age from 24 to 77 years, and the average duration of the infection was 3-7 days.

Symptoms were nonspecific and included fever, headache, fatigue, nausea, cough, and sore throat. All 86 patients were treated with intravenous ribavirin (0.5 g/day), and intramuscular benzylpenicillin sodium (2 million U/day) for 3-5 days. The median hospital stay was 11 days, and no deaths or long-term clinical complications occurred in the confirmed ALSV patients.

ALSV is similar to other jingmenviruses, but is distinct from other infections in part because of the absence of a rash or jaundice, the investigators said.

Although the investigators said they suspected the disease was carried by ticks, they would not rule out mosquitoes as a possible carrier because ALSV RNA was found in mosquitoes in a Northeastern province of China, and the RNA from those mosquitoes was found to be genetically related to the RNA assessed in this study.

Overall, “our findings suggest that ALSV may be the cause of a previously unknown febrile disease, and more studies should be conducted to determine the geographic distribution of this disease outside its current areas of identification,” they said.

The research was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
 

SOURCE: Wang Z et al. N Engl J Med. 2019 May 29. doi: 10.1056/NEJMoa1805068.

A new virus has been associated with febrile illness in China in patients with histories of tick bites. The data on the discovery, isolation, and characterization of the virus were reported in the New England Journal of Medicine.

The segmented RNA virus now known as Alongshan virus (ALSV) “belongs to the unclassified jingmenvirus group in the family Flaviviridae, which includes the genera flavivirus, pestivirus, hepacivirus, and pegivirus,” wrote Ze-Dong Wang, PhD, of Foshan (China) University, and colleagues.

The index patient with ALSV was a 42-year-old female farmer from the town of Alongshan, China, who presented to a regional hospital in April 2017 with fever, headache, and a history of tick bites. The initial clinical features were similar to those seen in tickborne diseases, but a blood sample showed no RNA or antibodies for tickborne encephalitis virus. Investigators obtained a blood specimen from the index patient 4 days after the onset of illness. After culturing the sample, the investigators extracted the viral RNA genome and sequenced it.

Sequence analysis found that the new pathogen was related to segmented viruses in the jingmenvirus group of the family Flaviviridae; however, “comparison of the amino acids further confirmed that ALSV is genetically distinct from other jingmenviruses,” the investigators said.

The investigators identified 374 patients who presented to the hospital with fever, headache, and a history of tick bites during May 2017–September 2017; 86 patients had confirmed ALSV infections via nested reverse-transcription polymerase chain reaction testing. Of these, 63 were men and 84 were farmers or forestry workers. Although ticks were common in the patients’ environments, no other evidence of tickborne diseases was noted. The patients ranged in age from 24 to 77 years, and the average duration of the infection was 3-7 days.

Symptoms were nonspecific and included fever, headache, fatigue, nausea, cough, and sore throat. All 86 patients were treated with intravenous ribavirin (0.5 g/day), and intramuscular benzylpenicillin sodium (2 million U/day) for 3-5 days. The median hospital stay was 11 days, and no deaths or long-term clinical complications occurred in the confirmed ALSV patients.

ALSV is similar to other jingmenviruses, but is distinct from other infections in part because of the absence of a rash or jaundice, the investigators said.

Although the investigators said they suspected the disease was carried by ticks, they would not rule out mosquitoes as a possible carrier because ALSV RNA was found in mosquitoes in a Northeastern province of China, and the RNA from those mosquitoes was found to be genetically related to the RNA assessed in this study.

Overall, “our findings suggest that ALSV may be the cause of a previously unknown febrile disease, and more studies should be conducted to determine the geographic distribution of this disease outside its current areas of identification,” they said.

The research was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
 

SOURCE: Wang Z et al. N Engl J Med. 2019 May 29. doi: 10.1056/NEJMoa1805068.

A new virus has been associated with febrile illness in China in patients with histories of tick bites. The data on the discovery, isolation, and characterization of the virus were reported in the New England Journal of Medicine.

The segmented RNA virus now known as Alongshan virus (ALSV) “belongs to the unclassified jingmenvirus group in the family Flaviviridae, which includes the genera flavivirus, pestivirus, hepacivirus, and pegivirus,” wrote Ze-Dong Wang, PhD, of Foshan (China) University, and colleagues.

The index patient with ALSV was a 42-year-old female farmer from the town of Alongshan, China, who presented to a regional hospital in April 2017 with fever, headache, and a history of tick bites. The initial clinical features were similar to those seen in tickborne diseases, but a blood sample showed no RNA or antibodies for tickborne encephalitis virus. Investigators obtained a blood specimen from the index patient 4 days after the onset of illness. After culturing the sample, the investigators extracted the viral RNA genome and sequenced it.

Sequence analysis found that the new pathogen was related to segmented viruses in the jingmenvirus group of the family Flaviviridae; however, “comparison of the amino acids further confirmed that ALSV is genetically distinct from other jingmenviruses,” the investigators said.

The investigators identified 374 patients who presented to the hospital with fever, headache, and a history of tick bites during May 2017–September 2017; 86 patients had confirmed ALSV infections via nested reverse-transcription polymerase chain reaction testing. Of these, 63 were men and 84 were farmers or forestry workers. Although ticks were common in the patients’ environments, no other evidence of tickborne diseases was noted. The patients ranged in age from 24 to 77 years, and the average duration of the infection was 3-7 days.

Symptoms were nonspecific and included fever, headache, fatigue, nausea, cough, and sore throat. All 86 patients were treated with intravenous ribavirin (0.5 g/day), and intramuscular benzylpenicillin sodium (2 million U/day) for 3-5 days. The median hospital stay was 11 days, and no deaths or long-term clinical complications occurred in the confirmed ALSV patients.

ALSV is similar to other jingmenviruses, but is distinct from other infections in part because of the absence of a rash or jaundice, the investigators said.

Although the investigators said they suspected the disease was carried by ticks, they would not rule out mosquitoes as a possible carrier because ALSV RNA was found in mosquitoes in a Northeastern province of China, and the RNA from those mosquitoes was found to be genetically related to the RNA assessed in this study.

Overall, “our findings suggest that ALSV may be the cause of a previously unknown febrile disease, and more studies should be conducted to determine the geographic distribution of this disease outside its current areas of identification,” they said.

The research was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
 

SOURCE: Wang Z et al. N Engl J Med. 2019 May 29. doi: 10.1056/NEJMoa1805068.

LJUBLJANA, SLOVENIA – There is good news and bad news about human papillomavirus (HPV) vaccination as a means of preventing cervical cancer.

Bruce Jancin/MDedge News

The bad news is the HPV vaccines are projected to be in short supply, unable to meet global demand until at least 2024. The good news is that mounting evidence strongly suggests that one HPV dose may provide durable protection – in one study, for 11 years and counting – which would effectively double the existing supply, Aimee R. Kreimer, PhD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

These data come from post hoc analyses of major phase 3 randomized controlled trials of bivalent HPV vaccine in Costa Rica and quadrivalent vaccine in India. However, these secondary analyses aren’t considered rock solid evidence because the subjects who got a single dose weren’t randomized to that strategy, they simply for one reason or another didn’t receive the recommended additional dose or doses.

“I don’t know if these studies are enough, so several studies have been launched over the past couple of years with an eye toward generating the quality of data that would be sufficient to motivate policy change, if in fact one dose is proven to be effective,” said Dr. Kreimer, a senior scientist at the National Cancer Institute in Bethesda, Md.

The first of these formal randomized, controlled trials – a delayed second-dose study in 9- to 11-year-old U.S. boys and girls – is due to be completed next year. Four other trials ongoing in Africa and Costa Rica, all in females, are expected to report findings in 2022-2025.

Dr. Kreimer is first author of a soon-to-be-published 11-year update from the phase 3 Costa Rica HPV Vaccine Trial, which was launched prior to licensure of the GlaxoSmithKline bivalent HPV vaccine. Previous analyses showed that at both 4 and 7 years of follow-up, a single dose of the vaccine was as effective as two or three in preventing infection with HPV types 16 and 18, which are covered by the vaccine.

“Now the research question has transitioned to, ‘Will one dose be sufficiently durable?’ she explained.

The answer from this study is yes. At 11 years since receipt of the bivalent HPV vaccine, there was no difference in terms of prevalent HPV 16/18 infection between the one-, two-, and three-dose groups. To address the issue of possible selection bias in this post hoc nonrandomized comparison, Dr. Kreimer and her coinvestigators looked at rates of infection with HPV 31 and 45, which aren’t covered by the vaccine. The rates were similar regardless of the number of vaccine doses received 11 years earlier, indicating women in all three dosing groups are at similar risk for acquiring HPV infection, thus bolstering the legitimacy of the conclusion that one dose provides effective long-term protection.

Intriguingly, HPV serum antibody levels in the single-dose group have remained stable for 11 years at a level that’s only about one-quarter of that associated with three doses of the vaccine, albeit an order of magnitude greater than the level induced by natural immunity.

“This really challenges the dogma of the HPV vaccine,” according to Dr. Kreimer. “It suggests that inferior [HPV] antibodies do not necessarily mean inferior protection.”

The explanation for this phenomenon appears to be that HPV subunit vaccine mimics the shell of authentic virions so well that the immune system sees it as dangerous and mounts long-term antibody production. Also, cervical infection by HPV is a relatively slow process, allowing time for vaccine-induced antibodies to interrupt it, she said.

In contrast to the encouraging findings from this post hoc analysis and another from a phase 3 trial of quadrivalent vaccine in India, numerous phase 4 vaccine effectiveness monitoring studies have shown markedly lower vaccine effectiveness for one dose of HPV vaccine. Dr. Kreimer cautioned that this is a flawed conclusion attributable to a methodologic artifact whereby the investigators have lumped together single-dose recipients who were 17 years old or more at the time with those who were younger.

“The problem is that many people who are aged 17-18 years already have HPV infection, so when they are vaccinated it shows up as a vaccine failure. That’s not correct. These are prophylactic HPV vaccines. They’re not meant to help clear an infection,” she noted.

Stepping back, Dr. Kreimer observed that cervical cancer “is really a story of inequality.” Indeed, 90% of cervical cancers occur in low-income countries, where HPV vaccination uptake remains very low even more than a decade after licensure. When modelers project out in the future, they estimate that at current HPV vaccination levels in Sub-Saharan Africa, which has the highest cervical cancer rates in the world, it would take more than 100 years to achieve the World Health Organization goal of eliminating the malignancy.

Asked by an audience member how low a single-dose vaccine effectiveness level she considers acceptable to help reach the goal of eliminating cervical cancer in developing countries, Dr. Kreimer cautioned against the tendency to let ‘perfect’ become the enemy of ‘good.’

“I’ll remind everyone that, in this moment, very few of the target girls in the lower– and upper-lower–income countries are getting any vaccination. So I don’t think it’s a question of whether we should be going from two to one dose, I think it’s really a question of, for those who are at zero doses, how do we get them one dose? And with the HPV vaccine, we’ve even seen suggestions of herd immunity if we have 50% uptake,” she replied.

Dr. Kreimer reported having no financial conflicts regarding her presentation.

[email protected]

LJUBLJANA, SLOVENIA – There is good news and bad news about human papillomavirus (HPV) vaccination as a means of preventing cervical cancer.

Bruce Jancin/MDedge News

The bad news is the HPV vaccines are projected to be in short supply, unable to meet global demand until at least 2024. The good news is that mounting evidence strongly suggests that one HPV dose may provide durable protection – in one study, for 11 years and counting – which would effectively double the existing supply, Aimee R. Kreimer, PhD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

These data come from post hoc analyses of major phase 3 randomized controlled trials of bivalent HPV vaccine in Costa Rica and quadrivalent vaccine in India. However, these secondary analyses aren’t considered rock solid evidence because the subjects who got a single dose weren’t randomized to that strategy, they simply for one reason or another didn’t receive the recommended additional dose or doses.

“I don’t know if these studies are enough, so several studies have been launched over the past couple of years with an eye toward generating the quality of data that would be sufficient to motivate policy change, if in fact one dose is proven to be effective,” said Dr. Kreimer, a senior scientist at the National Cancer Institute in Bethesda, Md.

The first of these formal randomized, controlled trials – a delayed second-dose study in 9- to 11-year-old U.S. boys and girls – is due to be completed next year. Four other trials ongoing in Africa and Costa Rica, all in females, are expected to report findings in 2022-2025.

Dr. Kreimer is first author of a soon-to-be-published 11-year update from the phase 3 Costa Rica HPV Vaccine Trial, which was launched prior to licensure of the GlaxoSmithKline bivalent HPV vaccine. Previous analyses showed that at both 4 and 7 years of follow-up, a single dose of the vaccine was as effective as two or three in preventing infection with HPV types 16 and 18, which are covered by the vaccine.

“Now the research question has transitioned to, ‘Will one dose be sufficiently durable?’ she explained.

The answer from this study is yes. At 11 years since receipt of the bivalent HPV vaccine, there was no difference in terms of prevalent HPV 16/18 infection between the one-, two-, and three-dose groups. To address the issue of possible selection bias in this post hoc nonrandomized comparison, Dr. Kreimer and her coinvestigators looked at rates of infection with HPV 31 and 45, which aren’t covered by the vaccine. The rates were similar regardless of the number of vaccine doses received 11 years earlier, indicating women in all three dosing groups are at similar risk for acquiring HPV infection, thus bolstering the legitimacy of the conclusion that one dose provides effective long-term protection.

Intriguingly, HPV serum antibody levels in the single-dose group have remained stable for 11 years at a level that’s only about one-quarter of that associated with three doses of the vaccine, albeit an order of magnitude greater than the level induced by natural immunity.

“This really challenges the dogma of the HPV vaccine,” according to Dr. Kreimer. “It suggests that inferior [HPV] antibodies do not necessarily mean inferior protection.”

The explanation for this phenomenon appears to be that HPV subunit vaccine mimics the shell of authentic virions so well that the immune system sees it as dangerous and mounts long-term antibody production. Also, cervical infection by HPV is a relatively slow process, allowing time for vaccine-induced antibodies to interrupt it, she said.

In contrast to the encouraging findings from this post hoc analysis and another from a phase 3 trial of quadrivalent vaccine in India, numerous phase 4 vaccine effectiveness monitoring studies have shown markedly lower vaccine effectiveness for one dose of HPV vaccine. Dr. Kreimer cautioned that this is a flawed conclusion attributable to a methodologic artifact whereby the investigators have lumped together single-dose recipients who were 17 years old or more at the time with those who were younger.

“The problem is that many people who are aged 17-18 years already have HPV infection, so when they are vaccinated it shows up as a vaccine failure. That’s not correct. These are prophylactic HPV vaccines. They’re not meant to help clear an infection,” she noted.

Stepping back, Dr. Kreimer observed that cervical cancer “is really a story of inequality.” Indeed, 90% of cervical cancers occur in low-income countries, where HPV vaccination uptake remains very low even more than a decade after licensure. When modelers project out in the future, they estimate that at current HPV vaccination levels in Sub-Saharan Africa, which has the highest cervical cancer rates in the world, it would take more than 100 years to achieve the World Health Organization goal of eliminating the malignancy.

Asked by an audience member how low a single-dose vaccine effectiveness level she considers acceptable to help reach the goal of eliminating cervical cancer in developing countries, Dr. Kreimer cautioned against the tendency to let ‘perfect’ become the enemy of ‘good.’

“I’ll remind everyone that, in this moment, very few of the target girls in the lower– and upper-lower–income countries are getting any vaccination. So I don’t think it’s a question of whether we should be going from two to one dose, I think it’s really a question of, for those who are at zero doses, how do we get them one dose? And with the HPV vaccine, we’ve even seen suggestions of herd immunity if we have 50% uptake,” she replied.

Dr. Kreimer reported having no financial conflicts regarding her presentation.

[email protected]

LJUBLJANA, SLOVENIA – There is good news and bad news about human papillomavirus (HPV) vaccination as a means of preventing cervical cancer.

Bruce Jancin/MDedge News

The bad news is the HPV vaccines are projected to be in short supply, unable to meet global demand until at least 2024. The good news is that mounting evidence strongly suggests that one HPV dose may provide durable protection – in one study, for 11 years and counting – which would effectively double the existing supply, Aimee R. Kreimer, PhD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

These data come from post hoc analyses of major phase 3 randomized controlled trials of bivalent HPV vaccine in Costa Rica and quadrivalent vaccine in India. However, these secondary analyses aren’t considered rock solid evidence because the subjects who got a single dose weren’t randomized to that strategy, they simply for one reason or another didn’t receive the recommended additional dose or doses.

“I don’t know if these studies are enough, so several studies have been launched over the past couple of years with an eye toward generating the quality of data that would be sufficient to motivate policy change, if in fact one dose is proven to be effective,” said Dr. Kreimer, a senior scientist at the National Cancer Institute in Bethesda, Md.

The first of these formal randomized, controlled trials – a delayed second-dose study in 9- to 11-year-old U.S. boys and girls – is due to be completed next year. Four other trials ongoing in Africa and Costa Rica, all in females, are expected to report findings in 2022-2025.

Dr. Kreimer is first author of a soon-to-be-published 11-year update from the phase 3 Costa Rica HPV Vaccine Trial, which was launched prior to licensure of the GlaxoSmithKline bivalent HPV vaccine. Previous analyses showed that at both 4 and 7 years of follow-up, a single dose of the vaccine was as effective as two or three in preventing infection with HPV types 16 and 18, which are covered by the vaccine.

“Now the research question has transitioned to, ‘Will one dose be sufficiently durable?’ she explained.

The answer from this study is yes. At 11 years since receipt of the bivalent HPV vaccine, there was no difference in terms of prevalent HPV 16/18 infection between the one-, two-, and three-dose groups. To address the issue of possible selection bias in this post hoc nonrandomized comparison, Dr. Kreimer and her coinvestigators looked at rates of infection with HPV 31 and 45, which aren’t covered by the vaccine. The rates were similar regardless of the number of vaccine doses received 11 years earlier, indicating women in all three dosing groups are at similar risk for acquiring HPV infection, thus bolstering the legitimacy of the conclusion that one dose provides effective long-term protection.

Intriguingly, HPV serum antibody levels in the single-dose group have remained stable for 11 years at a level that’s only about one-quarter of that associated with three doses of the vaccine, albeit an order of magnitude greater than the level induced by natural immunity.

“This really challenges the dogma of the HPV vaccine,” according to Dr. Kreimer. “It suggests that inferior [HPV] antibodies do not necessarily mean inferior protection.”

The explanation for this phenomenon appears to be that HPV subunit vaccine mimics the shell of authentic virions so well that the immune system sees it as dangerous and mounts long-term antibody production. Also, cervical infection by HPV is a relatively slow process, allowing time for vaccine-induced antibodies to interrupt it, she said.

In contrast to the encouraging findings from this post hoc analysis and another from a phase 3 trial of quadrivalent vaccine in India, numerous phase 4 vaccine effectiveness monitoring studies have shown markedly lower vaccine effectiveness for one dose of HPV vaccine. Dr. Kreimer cautioned that this is a flawed conclusion attributable to a methodologic artifact whereby the investigators have lumped together single-dose recipients who were 17 years old or more at the time with those who were younger.

“The problem is that many people who are aged 17-18 years already have HPV infection, so when they are vaccinated it shows up as a vaccine failure. That’s not correct. These are prophylactic HPV vaccines. They’re not meant to help clear an infection,” she noted.

Stepping back, Dr. Kreimer observed that cervical cancer “is really a story of inequality.” Indeed, 90% of cervical cancers occur in low-income countries, where HPV vaccination uptake remains very low even more than a decade after licensure. When modelers project out in the future, they estimate that at current HPV vaccination levels in Sub-Saharan Africa, which has the highest cervical cancer rates in the world, it would take more than 100 years to achieve the World Health Organization goal of eliminating the malignancy.

Asked by an audience member how low a single-dose vaccine effectiveness level she considers acceptable to help reach the goal of eliminating cervical cancer in developing countries, Dr. Kreimer cautioned against the tendency to let ‘perfect’ become the enemy of ‘good.’

“I’ll remind everyone that, in this moment, very few of the target girls in the lower– and upper-lower–income countries are getting any vaccination. So I don’t think it’s a question of whether we should be going from two to one dose, I think it’s really a question of, for those who are at zero doses, how do we get them one dose? And with the HPV vaccine, we’ve even seen suggestions of herd immunity if we have 50% uptake,” she replied.

Dr. Kreimer reported having no financial conflicts regarding her presentation.

[email protected]

A 10-valent pneumococcal conjugate vaccine appeared equally effective against pneumococcal disease in boys and girls, according to Heta Nieminen, MD, of the National Institute for Health and Welfare in Tampere, Finland, and associates.

MarianVejcik/Getty Images

For the study, published in Vaccine, the investigators conducted a post hoc analysis of the phase III/IV, cluster-randomized, double-blind FinIP trial, in which more than 30,000 infants received the PHiD-CV10 vaccine or a placebo. Patients were aged less than 7 months when they received their first vaccination, and received two or three primary doses, plus a booster shot after the age of 11 months (Vaccine. 2019 May 20. doi: 10.1016/j.vaccine.2019.05.033).

In term infants, vaccine effectiveness was similar in boys and girls; while the vaccine worked marginally better in girls, the difference was not significant. Infants who received the 2 + 1 schedule had vaccine effectiveness similar to that of those who received the 3 + 1 schedule. In a smaller subanalysis of 1,519 preterm infants, outcomes of pneumonia were more common, but the vaccine seemed to confer protection, although the sample size was not large enough for statistical significance to be reached.

“The point estimates of vaccine effectiveness suggest protection in both sexes, and also among the preterm and low-birth-weight infants. ... There were no significant differences between the 2 + 1 and 3 + 1 schedules in any of the subgroups analyzed. Based on this study, the 2 + 1 or “Nordic” schedule is sufficient also for the risk groups such as the preterm or low-birth-weight infants,” the investigators concluded.

Five study authors are employees of the National Institute for Health and Welfare, which received funding for the study from GlaxoSmithKline. Four coauthors are employees of GlaxoSmithKline; three of them own shares in the company.

[email protected]

A 10-valent pneumococcal conjugate vaccine appeared equally effective against pneumococcal disease in boys and girls, according to Heta Nieminen, MD, of the National Institute for Health and Welfare in Tampere, Finland, and associates.

MarianVejcik/Getty Images

For the study, published in Vaccine, the investigators conducted a post hoc analysis of the phase III/IV, cluster-randomized, double-blind FinIP trial, in which more than 30,000 infants received the PHiD-CV10 vaccine or a placebo. Patients were aged less than 7 months when they received their first vaccination, and received two or three primary doses, plus a booster shot after the age of 11 months (Vaccine. 2019 May 20. doi: 10.1016/j.vaccine.2019.05.033).

In term infants, vaccine effectiveness was similar in boys and girls; while the vaccine worked marginally better in girls, the difference was not significant. Infants who received the 2 + 1 schedule had vaccine effectiveness similar to that of those who received the 3 + 1 schedule. In a smaller subanalysis of 1,519 preterm infants, outcomes of pneumonia were more common, but the vaccine seemed to confer protection, although the sample size was not large enough for statistical significance to be reached.

“The point estimates of vaccine effectiveness suggest protection in both sexes, and also among the preterm and low-birth-weight infants. ... There were no significant differences between the 2 + 1 and 3 + 1 schedules in any of the subgroups analyzed. Based on this study, the 2 + 1 or “Nordic” schedule is sufficient also for the risk groups such as the preterm or low-birth-weight infants,” the investigators concluded.

Five study authors are employees of the National Institute for Health and Welfare, which received funding for the study from GlaxoSmithKline. Four coauthors are employees of GlaxoSmithKline; three of them own shares in the company.

[email protected]

A 10-valent pneumococcal conjugate vaccine appeared equally effective against pneumococcal disease in boys and girls, according to Heta Nieminen, MD, of the National Institute for Health and Welfare in Tampere, Finland, and associates.

MarianVejcik/Getty Images

For the study, published in Vaccine, the investigators conducted a post hoc analysis of the phase III/IV, cluster-randomized, double-blind FinIP trial, in which more than 30,000 infants received the PHiD-CV10 vaccine or a placebo. Patients were aged less than 7 months when they received their first vaccination, and received two or three primary doses, plus a booster shot after the age of 11 months (Vaccine. 2019 May 20. doi: 10.1016/j.vaccine.2019.05.033).

In term infants, vaccine effectiveness was similar in boys and girls; while the vaccine worked marginally better in girls, the difference was not significant. Infants who received the 2 + 1 schedule had vaccine effectiveness similar to that of those who received the 3 + 1 schedule. In a smaller subanalysis of 1,519 preterm infants, outcomes of pneumonia were more common, but the vaccine seemed to confer protection, although the sample size was not large enough for statistical significance to be reached.

“The point estimates of vaccine effectiveness suggest protection in both sexes, and also among the preterm and low-birth-weight infants. ... There were no significant differences between the 2 + 1 and 3 + 1 schedules in any of the subgroups analyzed. Based on this study, the 2 + 1 or “Nordic” schedule is sufficient also for the risk groups such as the preterm or low-birth-weight infants,” the investigators concluded.

Five study authors are employees of the National Institute for Health and Welfare, which received funding for the study from GlaxoSmithKline. Four coauthors are employees of GlaxoSmithKline; three of them own shares in the company.

[email protected]

Trimethoprim-sulfamethoxazole (TMP-SMX) was linked to severe acute respiratory distress syndrome (ARDS) in five previously healthy teens, two of whom died.

TMP-SMX, a frequently prescribed antibiotic, has been associated with “idiosyncratic adverse drug reactions, including cutaneous reactions and hypersensitivity syndromes,” but pulmonary complications are rare, especially in children, wrote Jenna O. Miller, MD, of the University of Missouri–Kansas City and colleagues.

In a case series published in Pediatrics, the researchers described the patients, who were aged 13-18 years; the 18-year-old was male, the others were female. Four of the patients (three females, one male) were taking TMP-SMX for acne vulgaris. One of these patients, a 13-year-old girl, underwent a bilateral lung and heart transplant after developing interstitial lung disease and died as a result of solid organ transplant complications. The other death occurred in a 15-year-old girl who was taking TMP-SMX to treat a urinary tract infection. This patient developed interstitial lung disease and died of complications from the disease while awaiting a lung transplant.

“In all cases, patients were transferred to academic medical facilities, and pediatric pulmonologists and infectious diseases specialists performed extensive evaluations,” the researchers wrote. The patients did not improve when the drug was discontinued, and four of the five were considered or listed for organ transplants. The spectrum of disease was varied among the patients, and the pathophysiology remains poorly understood.

Although no clinical test could confirm causality between TMP-SMX and ARDS in the five teens, “the extensive negative workup, paired with recent TMP-SMX exposure and similarity among these cases, raises the possibility that the observed ARDS was TMP-SMX triggered,” they wrote.

The researchers had no financial conflicts to disclose.

SOURCE: Miller JO et al. Pediatrics. 2019 May 29. doi: 10.1542/peds.2018.3242.

Trimethoprim-sulfamethoxazole (TMP-SMX) was linked to severe acute respiratory distress syndrome (ARDS) in five previously healthy teens, two of whom died.

TMP-SMX, a frequently prescribed antibiotic, has been associated with “idiosyncratic adverse drug reactions, including cutaneous reactions and hypersensitivity syndromes,” but pulmonary complications are rare, especially in children, wrote Jenna O. Miller, MD, of the University of Missouri–Kansas City and colleagues.

In a case series published in Pediatrics, the researchers described the patients, who were aged 13-18 years; the 18-year-old was male, the others were female. Four of the patients (three females, one male) were taking TMP-SMX for acne vulgaris. One of these patients, a 13-year-old girl, underwent a bilateral lung and heart transplant after developing interstitial lung disease and died as a result of solid organ transplant complications. The other death occurred in a 15-year-old girl who was taking TMP-SMX to treat a urinary tract infection. This patient developed interstitial lung disease and died of complications from the disease while awaiting a lung transplant.

“In all cases, patients were transferred to academic medical facilities, and pediatric pulmonologists and infectious diseases specialists performed extensive evaluations,” the researchers wrote. The patients did not improve when the drug was discontinued, and four of the five were considered or listed for organ transplants. The spectrum of disease was varied among the patients, and the pathophysiology remains poorly understood.

Although no clinical test could confirm causality between TMP-SMX and ARDS in the five teens, “the extensive negative workup, paired with recent TMP-SMX exposure and similarity among these cases, raises the possibility that the observed ARDS was TMP-SMX triggered,” they wrote.

The researchers had no financial conflicts to disclose.

SOURCE: Miller JO et al. Pediatrics. 2019 May 29. doi: 10.1542/peds.2018.3242.

Trimethoprim-sulfamethoxazole (TMP-SMX) was linked to severe acute respiratory distress syndrome (ARDS) in five previously healthy teens, two of whom died.

TMP-SMX, a frequently prescribed antibiotic, has been associated with “idiosyncratic adverse drug reactions, including cutaneous reactions and hypersensitivity syndromes,” but pulmonary complications are rare, especially in children, wrote Jenna O. Miller, MD, of the University of Missouri–Kansas City and colleagues.

In a case series published in Pediatrics, the researchers described the patients, who were aged 13-18 years; the 18-year-old was male, the others were female. Four of the patients (three females, one male) were taking TMP-SMX for acne vulgaris. One of these patients, a 13-year-old girl, underwent a bilateral lung and heart transplant after developing interstitial lung disease and died as a result of solid organ transplant complications. The other death occurred in a 15-year-old girl who was taking TMP-SMX to treat a urinary tract infection. This patient developed interstitial lung disease and died of complications from the disease while awaiting a lung transplant.

“In all cases, patients were transferred to academic medical facilities, and pediatric pulmonologists and infectious diseases specialists performed extensive evaluations,” the researchers wrote. The patients did not improve when the drug was discontinued, and four of the five were considered or listed for organ transplants. The spectrum of disease was varied among the patients, and the pathophysiology remains poorly understood.

Although no clinical test could confirm causality between TMP-SMX and ARDS in the five teens, “the extensive negative workup, paired with recent TMP-SMX exposure and similarity among these cases, raises the possibility that the observed ARDS was TMP-SMX triggered,” they wrote.

The researchers had no financial conflicts to disclose.

SOURCE: Miller JO et al. Pediatrics. 2019 May 29. doi: 10.1542/peds.2018.3242.

Having established that there is a documented increase in sexually transmitted infections (STIs) among older Americans, and furthermore recognizing that a contributing factor to this trend may be communication gaps between patients and their health care providers, I now want to address the “What do we do about it?” aspect of our discussion. As clinicians, we know that the core focus around infectious diseases of any kind is prevention.

There are 3 types of prevention, as noted by Fos and Fine in Introduction to Public Health, all of which fit into our current topic: primary (eliminating risk factors), secondary (early detection), and tertiary (eliminating or moderating disability associated with advanced disease).¹ The following recommendations fall into at least one of these categories.

1. All clinicians need to be involved in educating older Americans about the risks for STIs. Providers should routinely ask seniors if they are sexually active and should be prepared to recommend appropriate screening and education resources. Essentially, older adults should be getting the same basic “safe sex” education that younger people receive: learning about STIs, from recognizing the signs to understanding how STIs complicate other chronic medical conditions.^2,3

2. Seniors also need education on the importance—and proper use—of condoms. Furthermore, we should go a step further and ensure that free condoms are distributed in places where seniors live and congregate. People older than 60 report the lowest condom use of any population.^2,3

3. Information on STI detection and treatment options needs to be well publicized. For example, Medicare provides free STI screenings and low-cost treatments. We need to make sure our older patients are aware of this benefit and encourage them to make use of it.

4. Older Americans should be screened for STIs, regardless of age, per CDC guidelines. Seniors should get annual testing if they have new sexual partners—which means they must be asked the difficult questions.

And that’s the crux of the issue: Family members and clinicians may find it uncomfortable to have this conversation with Grandpa or Grandma. But there should be a dialogue to ensure they are aware of their risk for STIs, as well as how to prevent them.³ A well-known NP colleague reminded me of the importance of emphasizing to our older patients that anything discussed within the encounter is confidential and will not be disclosed without their permission. She starts off her conversations with patients by saying, “A lot of people your age experience …” or “Please don’t be insulted if I ask you about …” or “Is it OK if I ask you a few very personal questions?”

Continue to: It is critical...

It is critical to keep an open mind and accepting attitude when discussing sexuality or intimate issues with older patients. Paying attention to patients’ verbal and nonverbal cues is also essential. Clinicians should never assume older adults are sexually inactive, no longer care about sex, or are necessarily heterosexual. There was an excellent article in the Journal of Family Practice a few years ago on “How to discuss sex with elderly patients” that is worth rereading. In it, the authors suggest using the PLISSIT model to facilitate a conversation with your elderly patient. As explained in the article, the acronym “is a reminder to seek Permission to discuss sexuality, share Limited information about sexual issues that affect the older adult, provide Specific Suggestions to improve sexual health, and offer to provide a referral for Intensive Therapy if needed.”⁴ The Table offers some examples of how to address each step of PLISSIT.

So, as we wrap up our examination of this issue, I encourage you to open this dialogue with your older patients. In light of the increasing number of older patients with STIs, it is essential for clinicians to obtain an accurate and complete sexual history for patients of any age. That starts with asking the appropriate questions, preferably in a manner that puts the patient at ease to share important details. If you have additional ideas about what we can do to reverse this STI trend, please share them with me at [email protected].

Having established that there is a documented increase in sexually transmitted infections (STIs) among older Americans, and furthermore recognizing that a contributing factor to this trend may be communication gaps between patients and their health care providers, I now want to address the “What do we do about it?” aspect of our discussion. As clinicians, we know that the core focus around infectious diseases of any kind is prevention.

There are 3 types of prevention, as noted by Fos and Fine in Introduction to Public Health, all of which fit into our current topic: primary (eliminating risk factors), secondary (early detection), and tertiary (eliminating or moderating disability associated with advanced disease).¹ The following recommendations fall into at least one of these categories.

1. All clinicians need to be involved in educating older Americans about the risks for STIs. Providers should routinely ask seniors if they are sexually active and should be prepared to recommend appropriate screening and education resources. Essentially, older adults should be getting the same basic “safe sex” education that younger people receive: learning about STIs, from recognizing the signs to understanding how STIs complicate other chronic medical conditions.^2,3

2. Seniors also need education on the importance—and proper use—of condoms. Furthermore, we should go a step further and ensure that free condoms are distributed in places where seniors live and congregate. People older than 60 report the lowest condom use of any population.^2,3

3. Information on STI detection and treatment options needs to be well publicized. For example, Medicare provides free STI screenings and low-cost treatments. We need to make sure our older patients are aware of this benefit and encourage them to make use of it.

4. Older Americans should be screened for STIs, regardless of age, per CDC guidelines. Seniors should get annual testing if they have new sexual partners—which means they must be asked the difficult questions.

And that’s the crux of the issue: Family members and clinicians may find it uncomfortable to have this conversation with Grandpa or Grandma. But there should be a dialogue to ensure they are aware of their risk for STIs, as well as how to prevent them.³ A well-known NP colleague reminded me of the importance of emphasizing to our older patients that anything discussed within the encounter is confidential and will not be disclosed without their permission. She starts off her conversations with patients by saying, “A lot of people your age experience …” or “Please don’t be insulted if I ask you about …” or “Is it OK if I ask you a few very personal questions?”

Continue to: It is critical...

It is critical to keep an open mind and accepting attitude when discussing sexuality or intimate issues with older patients. Paying attention to patients’ verbal and nonverbal cues is also essential. Clinicians should never assume older adults are sexually inactive, no longer care about sex, or are necessarily heterosexual. There was an excellent article in the Journal of Family Practice a few years ago on “How to discuss sex with elderly patients” that is worth rereading. In it, the authors suggest using the PLISSIT model to facilitate a conversation with your elderly patient. As explained in the article, the acronym “is a reminder to seek Permission to discuss sexuality, share Limited information about sexual issues that affect the older adult, provide Specific Suggestions to improve sexual health, and offer to provide a referral for Intensive Therapy if needed.”⁴ The Table offers some examples of how to address each step of PLISSIT.

So, as we wrap up our examination of this issue, I encourage you to open this dialogue with your older patients. In light of the increasing number of older patients with STIs, it is essential for clinicians to obtain an accurate and complete sexual history for patients of any age. That starts with asking the appropriate questions, preferably in a manner that puts the patient at ease to share important details. If you have additional ideas about what we can do to reverse this STI trend, please share them with me at [email protected].

Having established that there is a documented increase in sexually transmitted infections (STIs) among older Americans, and furthermore recognizing that a contributing factor to this trend may be communication gaps between patients and their health care providers, I now want to address the “What do we do about it?” aspect of our discussion. As clinicians, we know that the core focus around infectious diseases of any kind is prevention.

There are 3 types of prevention, as noted by Fos and Fine in Introduction to Public Health, all of which fit into our current topic: primary (eliminating risk factors), secondary (early detection), and tertiary (eliminating or moderating disability associated with advanced disease).¹ The following recommendations fall into at least one of these categories.

1. All clinicians need to be involved in educating older Americans about the risks for STIs. Providers should routinely ask seniors if they are sexually active and should be prepared to recommend appropriate screening and education resources. Essentially, older adults should be getting the same basic “safe sex” education that younger people receive: learning about STIs, from recognizing the signs to understanding how STIs complicate other chronic medical conditions.^2,3

2. Seniors also need education on the importance—and proper use—of condoms. Furthermore, we should go a step further and ensure that free condoms are distributed in places where seniors live and congregate. People older than 60 report the lowest condom use of any population.^2,3

3. Information on STI detection and treatment options needs to be well publicized. For example, Medicare provides free STI screenings and low-cost treatments. We need to make sure our older patients are aware of this benefit and encourage them to make use of it.

4. Older Americans should be screened for STIs, regardless of age, per CDC guidelines. Seniors should get annual testing if they have new sexual partners—which means they must be asked the difficult questions.

And that’s the crux of the issue: Family members and clinicians may find it uncomfortable to have this conversation with Grandpa or Grandma. But there should be a dialogue to ensure they are aware of their risk for STIs, as well as how to prevent them.³ A well-known NP colleague reminded me of the importance of emphasizing to our older patients that anything discussed within the encounter is confidential and will not be disclosed without their permission. She starts off her conversations with patients by saying, “A lot of people your age experience …” or “Please don’t be insulted if I ask you about …” or “Is it OK if I ask you a few very personal questions?”

Continue to: It is critical...

It is critical to keep an open mind and accepting attitude when discussing sexuality or intimate issues with older patients. Paying attention to patients’ verbal and nonverbal cues is also essential. Clinicians should never assume older adults are sexually inactive, no longer care about sex, or are necessarily heterosexual. There was an excellent article in the Journal of Family Practice a few years ago on “How to discuss sex with elderly patients” that is worth rereading. In it, the authors suggest using the PLISSIT model to facilitate a conversation with your elderly patient. As explained in the article, the acronym “is a reminder to seek Permission to discuss sexuality, share Limited information about sexual issues that affect the older adult, provide Specific Suggestions to improve sexual health, and offer to provide a referral for Intensive Therapy if needed.”⁴ The Table offers some examples of how to address each step of PLISSIT.

So, as we wrap up our examination of this issue, I encourage you to open this dialogue with your older patients. In light of the increasing number of older patients with STIs, it is essential for clinicians to obtain an accurate and complete sexual history for patients of any age. That starts with asking the appropriate questions, preferably in a manner that puts the patient at ease to share important details. If you have additional ideas about what we can do to reverse this STI trend, please share them with me at [email protected].

LJUBLJANA, SLOVENIA – Don’t hold your breath waiting for a substantially better, more reliably effective influenza vaccine.

Bruce Jancin/MDedge News

That was a key cautionary message provided by vaccine expert Edward A. Belongia, MD, at the annual meeting of the European Society for Paediatric Infectious Diseases.

The effectiveness of seasonal influenza vaccine varies from 10% to 60% year by year, leaving enormous room for improvement. But many obstacles exist to developing a more consistent and reliably effective version of the seasonal influenza vaccine. And the lofty goal of creating a universal vaccine is even more ambitious, although the National Institute of Allergy and Infectious Diseases has declared it to be a top priority and mapped out a strategic plan for getting there (J Infect Dis. 2018 Jul 2;218[3]:347-54).

“Ultimately the Holy Grail is a universal flu vaccine that would provide pan-A and pan-B protection that would last for more than 1 year, with protection against avian and pandemic viruses, and would work for both children and adults. We are nowhere near that. Every 5 years someone says we’re 5 years away, and then 5 years go by and we’re still 5 years away. So I’m not making any predictions on that,” said Dr. Belongia, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wisc.) Clinic Research Institute, which is part of the U.S. Influenza Vaccine Effectiveness Network.

One of the big problems in creating a more effective flu vaccine, particularly for children, is the H3N2 virus subtype. Dr. Belongia was first author of a systematic review and meta-analysis of studies of more than a dozen recent flu seasons showing that although vaccine effectiveness against H3N2 varied widely from year to year, it was consistently lower than against influenza type B and H1N1 (Lancet Infect Dis. 2016 Aug;16[8]:942-51).

And that’s especially true in children and adolescents. Notably, in the 2014-2015 U.S. flu season, vaccine effectiveness against H3N2 in children aged 6 months to 8 years was low at 23%, but shockingly lower at a mere 7% in the 9- to 17-year-olds. Whereas in the 2017-2018 season, vaccine effectiveness against H3N2 in the 9- to 17-year-olds jumped to 46% while remaining low but consistent at 22% in the younger children.

“We see a very different age pattern here for the older children compared to the younger children, and quite frankly we don’t really understand what’s doing this,” said Dr. Belongia.

What is well understood, however, is that the problematic performance of influenza vaccines when it comes to protecting against H3N2 is a complicated matter stemming from three sources: the virus itself; the current egg-based vaccine manufacturing methodology, which is now 7 decades old; and host factors.


 

That troublesome H3N2 virus

Antigenic evolution of the H3N2 virus occurs at a 5- to 6-fold higher rate than for influenza B virus and roughly 17-fold faster than for H1N1. That high mutation rate makes for a moving target that’s a real problem when trying to keep a vaccine current. Also, the globular head of the virus is prone to glycosylation, which enables the virus to evade immune detection.

Vaccine-related factors

It’s likely that the availability of the flu vaccine for the upcoming 2019-2020 season is going to be delayed because of late selection of the strains for inclusion. The World Health Organization ordinarily selects strains for vaccines for the Northern Hemisphere in February, giving vaccine manufacturers 6-8 months to produce their vaccines and ship them in time for administration from September through November. This year, however, the WHO delayed selection of the H3N2 component until March because of the high level of antigenic and genetic diversity of circulating strains.

“This hasn’t happened since 2003 – it’s a very rare occurrence – but it does increase the potential that there’s going to be a delay in the availability of the vaccine in the fall,” he explained.

Eventually, the WHO selected a new clade 3C.3a virus called A/Kansas/14/2017 for the 2019-2020 vaccine. It should cover the circulating strains of H3N2 “reasonably well,” according to the physician.

Another issue: H3N2 has become adapted to the mammalian environment, so growing the virus in eggs introduces strong selection pressure for mutations leading to reduced vaccine effectiveness. Yet only two flu vaccines licensed in the United States are manufactured without eggs: Flucelvax, marketed by Seqirus for patients aged 4 years and up, and Sanofi’s Flublok, which is licensed for individuals who are 18 years of age or older. Studies are underway looking at the relative effectiveness of egg-based versus cell culture-manufactured flu vaccines in real-world settings.
 

Host factors

Hemagglutinin imprinting, sometimes referred to as “original antigenic sin,” is a decades-old concept whereby early childhood exposure to influenza viruses shapes future vaccine response.

“It suggests there could be some birth cohort effects in vaccine responsiveness, depending on what was circulating in the first 2-3 years after birth. It would complicate vaccine strategy quite a bit if you had to have different strategies for different birth cohorts,” Dr. Belongia observed.

Another host factor issue is the controversial topic of negative interference stemming from repeated vaccinations. It’s unclear how important this is in the real world, because studies have been inconsistent. Reassuringly, Dr. Belongia and coworkers found no association between prior-season influenza vaccination and diminished vaccine effectiveness in 3,369 U.S. children aged 2-17 years studied during the 2013-14 through 2015-16 flu seasons (JAMA Netw Open. 2018 Oct 5;1[6]:e183742. doi: 10.1001/jamanetworkopen.2018.3742).

“We found no suggestion at all of a problem with being vaccinated two seasons in a row,” according to Dr. Belongia.


 

How to build a better influenza vaccine for children

“I would say that even before we get to a universal vaccine, the next generation of flu vaccines that are more effective are not going to be manufactured using eggs, although we’re not real close to that. But I think that’s eventually where we’re going,” he said.

“I think it’s going to take a systems biology approach in order to really understand the adaptive immune response to infection and vaccination in early life. That means a much more detailed understanding of what is underlying the imprinting mechanisms and what is the adaptive response to repeated vaccination and infection. I think this is going to take prospective infant cohort studies; the National Institutes of Health is funding some that will begin within the next year,” Dr. Belongia added.

Many investigational approaches to improving influenza virus subtype-level protection are being explored. These include novel adjuvants, nanoparticle vaccines, computationally optimized broadly reactive antigens, and standardization of neuraminidase content.

And as for the much-desired universal flu vaccine?

“I will say that if a universal vaccine is going to work it’s probably going to work first in children. They have a much shorter immune history and their antibody landscape is a lot smaller, so you have a much better opportunity, I think, to generate a broad response to a universal vaccine compared to adults, who have much more complex immune landscapes,” he said.

Dr. Belongia reported having no financial conflicts regarding his presentation.

[email protected]

LJUBLJANA, SLOVENIA – Don’t hold your breath waiting for a substantially better, more reliably effective influenza vaccine.

Bruce Jancin/MDedge News

That was a key cautionary message provided by vaccine expert Edward A. Belongia, MD, at the annual meeting of the European Society for Paediatric Infectious Diseases.

The effectiveness of seasonal influenza vaccine varies from 10% to 60% year by year, leaving enormous room for improvement. But many obstacles exist to developing a more consistent and reliably effective version of the seasonal influenza vaccine. And the lofty goal of creating a universal vaccine is even more ambitious, although the National Institute of Allergy and Infectious Diseases has declared it to be a top priority and mapped out a strategic plan for getting there (J Infect Dis. 2018 Jul 2;218[3]:347-54).

“Ultimately the Holy Grail is a universal flu vaccine that would provide pan-A and pan-B protection that would last for more than 1 year, with protection against avian and pandemic viruses, and would work for both children and adults. We are nowhere near that. Every 5 years someone says we’re 5 years away, and then 5 years go by and we’re still 5 years away. So I’m not making any predictions on that,” said Dr. Belongia, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wisc.) Clinic Research Institute, which is part of the U.S. Influenza Vaccine Effectiveness Network.

One of the big problems in creating a more effective flu vaccine, particularly for children, is the H3N2 virus subtype. Dr. Belongia was first author of a systematic review and meta-analysis of studies of more than a dozen recent flu seasons showing that although vaccine effectiveness against H3N2 varied widely from year to year, it was consistently lower than against influenza type B and H1N1 (Lancet Infect Dis. 2016 Aug;16[8]:942-51).

And that’s especially true in children and adolescents. Notably, in the 2014-2015 U.S. flu season, vaccine effectiveness against H3N2 in children aged 6 months to 8 years was low at 23%, but shockingly lower at a mere 7% in the 9- to 17-year-olds. Whereas in the 2017-2018 season, vaccine effectiveness against H3N2 in the 9- to 17-year-olds jumped to 46% while remaining low but consistent at 22% in the younger children.

“We see a very different age pattern here for the older children compared to the younger children, and quite frankly we don’t really understand what’s doing this,” said Dr. Belongia.

What is well understood, however, is that the problematic performance of influenza vaccines when it comes to protecting against H3N2 is a complicated matter stemming from three sources: the virus itself; the current egg-based vaccine manufacturing methodology, which is now 7 decades old; and host factors.


 

That troublesome H3N2 virus

Antigenic evolution of the H3N2 virus occurs at a 5- to 6-fold higher rate than for influenza B virus and roughly 17-fold faster than for H1N1. That high mutation rate makes for a moving target that’s a real problem when trying to keep a vaccine current. Also, the globular head of the virus is prone to glycosylation, which enables the virus to evade immune detection.

Vaccine-related factors

It’s likely that the availability of the flu vaccine for the upcoming 2019-2020 season is going to be delayed because of late selection of the strains for inclusion. The World Health Organization ordinarily selects strains for vaccines for the Northern Hemisphere in February, giving vaccine manufacturers 6-8 months to produce their vaccines and ship them in time for administration from September through November. This year, however, the WHO delayed selection of the H3N2 component until March because of the high level of antigenic and genetic diversity of circulating strains.

“This hasn’t happened since 2003 – it’s a very rare occurrence – but it does increase the potential that there’s going to be a delay in the availability of the vaccine in the fall,” he explained.

Eventually, the WHO selected a new clade 3C.3a virus called A/Kansas/14/2017 for the 2019-2020 vaccine. It should cover the circulating strains of H3N2 “reasonably well,” according to the physician.

Another issue: H3N2 has become adapted to the mammalian environment, so growing the virus in eggs introduces strong selection pressure for mutations leading to reduced vaccine effectiveness. Yet only two flu vaccines licensed in the United States are manufactured without eggs: Flucelvax, marketed by Seqirus for patients aged 4 years and up, and Sanofi’s Flublok, which is licensed for individuals who are 18 years of age or older. Studies are underway looking at the relative effectiveness of egg-based versus cell culture-manufactured flu vaccines in real-world settings.
 

Host factors

Hemagglutinin imprinting, sometimes referred to as “original antigenic sin,” is a decades-old concept whereby early childhood exposure to influenza viruses shapes future vaccine response.

“It suggests there could be some birth cohort effects in vaccine responsiveness, depending on what was circulating in the first 2-3 years after birth. It would complicate vaccine strategy quite a bit if you had to have different strategies for different birth cohorts,” Dr. Belongia observed.

Another host factor issue is the controversial topic of negative interference stemming from repeated vaccinations. It’s unclear how important this is in the real world, because studies have been inconsistent. Reassuringly, Dr. Belongia and coworkers found no association between prior-season influenza vaccination and diminished vaccine effectiveness in 3,369 U.S. children aged 2-17 years studied during the 2013-14 through 2015-16 flu seasons (JAMA Netw Open. 2018 Oct 5;1[6]:e183742. doi: 10.1001/jamanetworkopen.2018.3742).

“We found no suggestion at all of a problem with being vaccinated two seasons in a row,” according to Dr. Belongia.


 

How to build a better influenza vaccine for children

“I would say that even before we get to a universal vaccine, the next generation of flu vaccines that are more effective are not going to be manufactured using eggs, although we’re not real close to that. But I think that’s eventually where we’re going,” he said.

“I think it’s going to take a systems biology approach in order to really understand the adaptive immune response to infection and vaccination in early life. That means a much more detailed understanding of what is underlying the imprinting mechanisms and what is the adaptive response to repeated vaccination and infection. I think this is going to take prospective infant cohort studies; the National Institutes of Health is funding some that will begin within the next year,” Dr. Belongia added.

Many investigational approaches to improving influenza virus subtype-level protection are being explored. These include novel adjuvants, nanoparticle vaccines, computationally optimized broadly reactive antigens, and standardization of neuraminidase content.

And as for the much-desired universal flu vaccine?

“I will say that if a universal vaccine is going to work it’s probably going to work first in children. They have a much shorter immune history and their antibody landscape is a lot smaller, so you have a much better opportunity, I think, to generate a broad response to a universal vaccine compared to adults, who have much more complex immune landscapes,” he said.

Dr. Belongia reported having no financial conflicts regarding his presentation.

[email protected]

LJUBLJANA, SLOVENIA – Don’t hold your breath waiting for a substantially better, more reliably effective influenza vaccine.

Bruce Jancin/MDedge News

That was a key cautionary message provided by vaccine expert Edward A. Belongia, MD, at the annual meeting of the European Society for Paediatric Infectious Diseases.

The effectiveness of seasonal influenza vaccine varies from 10% to 60% year by year, leaving enormous room for improvement. But many obstacles exist to developing a more consistent and reliably effective version of the seasonal influenza vaccine. And the lofty goal of creating a universal vaccine is even more ambitious, although the National Institute of Allergy and Infectious Diseases has declared it to be a top priority and mapped out a strategic plan for getting there (J Infect Dis. 2018 Jul 2;218[3]:347-54).

“Ultimately the Holy Grail is a universal flu vaccine that would provide pan-A and pan-B protection that would last for more than 1 year, with protection against avian and pandemic viruses, and would work for both children and adults. We are nowhere near that. Every 5 years someone says we’re 5 years away, and then 5 years go by and we’re still 5 years away. So I’m not making any predictions on that,” said Dr. Belongia, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wisc.) Clinic Research Institute, which is part of the U.S. Influenza Vaccine Effectiveness Network.

One of the big problems in creating a more effective flu vaccine, particularly for children, is the H3N2 virus subtype. Dr. Belongia was first author of a systematic review and meta-analysis of studies of more than a dozen recent flu seasons showing that although vaccine effectiveness against H3N2 varied widely from year to year, it was consistently lower than against influenza type B and H1N1 (Lancet Infect Dis. 2016 Aug;16[8]:942-51).

And that’s especially true in children and adolescents. Notably, in the 2014-2015 U.S. flu season, vaccine effectiveness against H3N2 in children aged 6 months to 8 years was low at 23%, but shockingly lower at a mere 7% in the 9- to 17-year-olds. Whereas in the 2017-2018 season, vaccine effectiveness against H3N2 in the 9- to 17-year-olds jumped to 46% while remaining low but consistent at 22% in the younger children.

“We see a very different age pattern here for the older children compared to the younger children, and quite frankly we don’t really understand what’s doing this,” said Dr. Belongia.

What is well understood, however, is that the problematic performance of influenza vaccines when it comes to protecting against H3N2 is a complicated matter stemming from three sources: the virus itself; the current egg-based vaccine manufacturing methodology, which is now 7 decades old; and host factors.


 

That troublesome H3N2 virus

Antigenic evolution of the H3N2 virus occurs at a 5- to 6-fold higher rate than for influenza B virus and roughly 17-fold faster than for H1N1. That high mutation rate makes for a moving target that’s a real problem when trying to keep a vaccine current. Also, the globular head of the virus is prone to glycosylation, which enables the virus to evade immune detection.

Vaccine-related factors

It’s likely that the availability of the flu vaccine for the upcoming 2019-2020 season is going to be delayed because of late selection of the strains for inclusion. The World Health Organization ordinarily selects strains for vaccines for the Northern Hemisphere in February, giving vaccine manufacturers 6-8 months to produce their vaccines and ship them in time for administration from September through November. This year, however, the WHO delayed selection of the H3N2 component until March because of the high level of antigenic and genetic diversity of circulating strains.

“This hasn’t happened since 2003 – it’s a very rare occurrence – but it does increase the potential that there’s going to be a delay in the availability of the vaccine in the fall,” he explained.

Eventually, the WHO selected a new clade 3C.3a virus called A/Kansas/14/2017 for the 2019-2020 vaccine. It should cover the circulating strains of H3N2 “reasonably well,” according to the physician.

Another issue: H3N2 has become adapted to the mammalian environment, so growing the virus in eggs introduces strong selection pressure for mutations leading to reduced vaccine effectiveness. Yet only two flu vaccines licensed in the United States are manufactured without eggs: Flucelvax, marketed by Seqirus for patients aged 4 years and up, and Sanofi’s Flublok, which is licensed for individuals who are 18 years of age or older. Studies are underway looking at the relative effectiveness of egg-based versus cell culture-manufactured flu vaccines in real-world settings.
 

Host factors

Hemagglutinin imprinting, sometimes referred to as “original antigenic sin,” is a decades-old concept whereby early childhood exposure to influenza viruses shapes future vaccine response.

“It suggests there could be some birth cohort effects in vaccine responsiveness, depending on what was circulating in the first 2-3 years after birth. It would complicate vaccine strategy quite a bit if you had to have different strategies for different birth cohorts,” Dr. Belongia observed.

Another host factor issue is the controversial topic of negative interference stemming from repeated vaccinations. It’s unclear how important this is in the real world, because studies have been inconsistent. Reassuringly, Dr. Belongia and coworkers found no association between prior-season influenza vaccination and diminished vaccine effectiveness in 3,369 U.S. children aged 2-17 years studied during the 2013-14 through 2015-16 flu seasons (JAMA Netw Open. 2018 Oct 5;1[6]:e183742. doi: 10.1001/jamanetworkopen.2018.3742).

“We found no suggestion at all of a problem with being vaccinated two seasons in a row,” according to Dr. Belongia.


 

How to build a better influenza vaccine for children

“I would say that even before we get to a universal vaccine, the next generation of flu vaccines that are more effective are not going to be manufactured using eggs, although we’re not real close to that. But I think that’s eventually where we’re going,” he said.

“I think it’s going to take a systems biology approach in order to really understand the adaptive immune response to infection and vaccination in early life. That means a much more detailed understanding of what is underlying the imprinting mechanisms and what is the adaptive response to repeated vaccination and infection. I think this is going to take prospective infant cohort studies; the National Institutes of Health is funding some that will begin within the next year,” Dr. Belongia added.

Many investigational approaches to improving influenza virus subtype-level protection are being explored. These include novel adjuvants, nanoparticle vaccines, computationally optimized broadly reactive antigens, and standardization of neuraminidase content.

And as for the much-desired universal flu vaccine?

“I will say that if a universal vaccine is going to work it’s probably going to work first in children. They have a much shorter immune history and their antibody landscape is a lot smaller, so you have a much better opportunity, I think, to generate a broad response to a universal vaccine compared to adults, who have much more complex immune landscapes,” he said.

Dr. Belongia reported having no financial conflicts regarding his presentation.

[email protected]

The year’s first cases of measles in Maine and New Mexico bring the total number of states with the virus to 26 in 2019, according to the Centers for Disease Control and Prevention.

The CDC received reports of 60 new measles cases last week – up from 41 the previous week – bringing the U.S. total to 940 for the year as of May 24. The CDC is currently tracking 10 outbreaks in seven states: California (3), Georgia, Maryland, Michigan, New York (2), Pennsylvania, and Washington.


The Maine Center for Disease Control and Prevention confirmed the state’s first case on May 20. The school-aged child from Somerset County had been vaccinated and is fully recovered from the disease. It’s not yet known where the child was exposed to measles, but sporadic cases are not unexpected, the Maine CDC said.

New Mexico’s first measles case of the year, a 1-year-old in Sierra County, has at least one state lawmaker considering changes to the state’s immunization exemption laws, the Farmington Daily Times reported.

[email protected]

The year’s first cases of measles in Maine and New Mexico bring the total number of states with the virus to 26 in 2019, according to the Centers for Disease Control and Prevention.

The CDC received reports of 60 new measles cases last week – up from 41 the previous week – bringing the U.S. total to 940 for the year as of May 24. The CDC is currently tracking 10 outbreaks in seven states: California (3), Georgia, Maryland, Michigan, New York (2), Pennsylvania, and Washington.


The Maine Center for Disease Control and Prevention confirmed the state’s first case on May 20. The school-aged child from Somerset County had been vaccinated and is fully recovered from the disease. It’s not yet known where the child was exposed to measles, but sporadic cases are not unexpected, the Maine CDC said.

New Mexico’s first measles case of the year, a 1-year-old in Sierra County, has at least one state lawmaker considering changes to the state’s immunization exemption laws, the Farmington Daily Times reported.

[email protected]

The year’s first cases of measles in Maine and New Mexico bring the total number of states with the virus to 26 in 2019, according to the Centers for Disease Control and Prevention.

The CDC received reports of 60 new measles cases last week – up from 41 the previous week – bringing the U.S. total to 940 for the year as of May 24. The CDC is currently tracking 10 outbreaks in seven states: California (3), Georgia, Maryland, Michigan, New York (2), Pennsylvania, and Washington.


The Maine Center for Disease Control and Prevention confirmed the state’s first case on May 20. The school-aged child from Somerset County had been vaccinated and is fully recovered from the disease. It’s not yet known where the child was exposed to measles, but sporadic cases are not unexpected, the Maine CDC said.

New Mexico’s first measles case of the year, a 1-year-old in Sierra County, has at least one state lawmaker considering changes to the state’s immunization exemption laws, the Farmington Daily Times reported.

[email protected]

Almost 10% of patients hospitalized with a dermatologic diagnosis are readmitted within 30 days, based on a national sample of 3.6 million skin-related hospitalizations.

Data from the Nationwide Readmissions Database also showed that the same-cause readmission rate was 3.3% after 30 days and 7.8% within the calendar year (CY) over the 5-year study period of 2010-2014, Myron Zhang, MD, of the department of dermatology at Weill Cornell Medicine, New York, and his associates reported in the Journal of the American Academy of Dermatology.

The total cost of the CY readmissions was $2.54 billion, which works out to $508 million per year or $8,995 per visit. The most common dermatologic diagnosis – cellulitis made up 83.6% of all hospitalizations – was also the most expensive in terms of readmissions, resulting in $1.9 billion in CY costs, Dr. Zhang and associates wrote.

Overall readmission rates for cellulitis were not provided, but annual rates ranged from 9.1% to 9.3% (30-day all cause), from 7.7% to 8.1% (CY same cause), and from 3.1% to 3.3% (30-day same cause), they wrote.

The dermatologic diagnosis with the highest 30-day same-cause readmission rate was vascular hamartomas at 21.1%, followed by dermatomyositis (18.3%) and thrombotic microangiopathy (13.7%). Dermatomyositis had the highest CY same-cause readmission rate (30.8%) and mycosis fungoides had the highest 30-day all-cause rate (32.3%), according to the investigators.

“Diseases, characteristics, and comorbidities associated with high readmission rates should trigger hospitals to consider dermatology consultation, coordinate outpatient follow-up, and support underinsured outpatient access. These measures have been shown to reduce readmissions or hospital visits in general dermatologic settings, but outcomes in individual diseases are not well studied,” Dr. Zhang and associates wrote. They noted that there have been “very few prior studies of readmissions for skin diseases.”

[email protected]

SOURCE: Zhang M et al. J Am Acad. Dermatol. 2019. doi: 10.1016/j.jaad.2019.05.023. .

Almost 10% of patients hospitalized with a dermatologic diagnosis are readmitted within 30 days, based on a national sample of 3.6 million skin-related hospitalizations.

Data from the Nationwide Readmissions Database also showed that the same-cause readmission rate was 3.3% after 30 days and 7.8% within the calendar year (CY) over the 5-year study period of 2010-2014, Myron Zhang, MD, of the department of dermatology at Weill Cornell Medicine, New York, and his associates reported in the Journal of the American Academy of Dermatology.

The total cost of the CY readmissions was $2.54 billion, which works out to $508 million per year or $8,995 per visit. The most common dermatologic diagnosis – cellulitis made up 83.6% of all hospitalizations – was also the most expensive in terms of readmissions, resulting in $1.9 billion in CY costs, Dr. Zhang and associates wrote.

Overall readmission rates for cellulitis were not provided, but annual rates ranged from 9.1% to 9.3% (30-day all cause), from 7.7% to 8.1% (CY same cause), and from 3.1% to 3.3% (30-day same cause), they wrote.

The dermatologic diagnosis with the highest 30-day same-cause readmission rate was vascular hamartomas at 21.1%, followed by dermatomyositis (18.3%) and thrombotic microangiopathy (13.7%). Dermatomyositis had the highest CY same-cause readmission rate (30.8%) and mycosis fungoides had the highest 30-day all-cause rate (32.3%), according to the investigators.

“Diseases, characteristics, and comorbidities associated with high readmission rates should trigger hospitals to consider dermatology consultation, coordinate outpatient follow-up, and support underinsured outpatient access. These measures have been shown to reduce readmissions or hospital visits in general dermatologic settings, but outcomes in individual diseases are not well studied,” Dr. Zhang and associates wrote. They noted that there have been “very few prior studies of readmissions for skin diseases.”

[email protected]

SOURCE: Zhang M et al. J Am Acad. Dermatol. 2019. doi: 10.1016/j.jaad.2019.05.023. .

Almost 10% of patients hospitalized with a dermatologic diagnosis are readmitted within 30 days, based on a national sample of 3.6 million skin-related hospitalizations.

Data from the Nationwide Readmissions Database also showed that the same-cause readmission rate was 3.3% after 30 days and 7.8% within the calendar year (CY) over the 5-year study period of 2010-2014, Myron Zhang, MD, of the department of dermatology at Weill Cornell Medicine, New York, and his associates reported in the Journal of the American Academy of Dermatology.

The total cost of the CY readmissions was $2.54 billion, which works out to $508 million per year or $8,995 per visit. The most common dermatologic diagnosis – cellulitis made up 83.6% of all hospitalizations – was also the most expensive in terms of readmissions, resulting in $1.9 billion in CY costs, Dr. Zhang and associates wrote.

Overall readmission rates for cellulitis were not provided, but annual rates ranged from 9.1% to 9.3% (30-day all cause), from 7.7% to 8.1% (CY same cause), and from 3.1% to 3.3% (30-day same cause), they wrote.

The dermatologic diagnosis with the highest 30-day same-cause readmission rate was vascular hamartomas at 21.1%, followed by dermatomyositis (18.3%) and thrombotic microangiopathy (13.7%). Dermatomyositis had the highest CY same-cause readmission rate (30.8%) and mycosis fungoides had the highest 30-day all-cause rate (32.3%), according to the investigators.

“Diseases, characteristics, and comorbidities associated with high readmission rates should trigger hospitals to consider dermatology consultation, coordinate outpatient follow-up, and support underinsured outpatient access. These measures have been shown to reduce readmissions or hospital visits in general dermatologic settings, but outcomes in individual diseases are not well studied,” Dr. Zhang and associates wrote. They noted that there have been “very few prior studies of readmissions for skin diseases.”

[email protected]

SOURCE: Zhang M et al. J Am Acad. Dermatol. 2019. doi: 10.1016/j.jaad.2019.05.023. .

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

The Food and Drug Administration has granted its first marketing clearance for extragenital diagnostic tests for chlamydia and gonorrhea.

The new tests, the Aptima Combo 2 Assay and Xpert CT/NG, use samples from the throat and rectum to test for chlamydia and gonorrhea, according to a statement from the FDA.

“It is best for patients if both [chlamydia and gonorrhea] are caught and treated right away, as significant complications can occur if left untreated,” noted Tim Stenzel, MD, in the statement.

“Today’s clearances provide a mechanism for more easily diagnosing these infections,” said Dr. Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health.

The two tests were reviewed through the premarket notification – or 510(k) – pathway, which seeks to demonstrate to the FDA that the device to be marketed is equivalent or better in safety and effectiveness to the legally marketed device.

In the FDA’s evaluation of the tests, it reviewed clinical data from a multisite study of more than 2,500 patients. This study evaluated the diagnostic accuracy of multiple commercially available nucleic acid amplification tests for detection of Neisseria gonorrhoeae and Chlamydia trachomatis from throat and rectal sites. The results of this study and other information reviewed by the FDA demonstrated that the two tests “are safe and effective for extragenital testing for chlamydia and gonorrhea,” according to the statement.

The data were collected through a cross-sectional study coordinated by the Antibacterial Resistance Leadership Group, which is funded and supported by the National Institute of Allergy and Infectious Diseases.

The FDA granted marketing clearance to Hologic and Cepheid for the Aptima Combo 2 Assay and the Xpert CT/NG, respectively.
 

[email protected]

The Food and Drug Administration has granted its first marketing clearance for extragenital diagnostic tests for chlamydia and gonorrhea.

The new tests, the Aptima Combo 2 Assay and Xpert CT/NG, use samples from the throat and rectum to test for chlamydia and gonorrhea, according to a statement from the FDA.

“It is best for patients if both [chlamydia and gonorrhea] are caught and treated right away, as significant complications can occur if left untreated,” noted Tim Stenzel, MD, in the statement.

“Today’s clearances provide a mechanism for more easily diagnosing these infections,” said Dr. Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health.

The two tests were reviewed through the premarket notification – or 510(k) – pathway, which seeks to demonstrate to the FDA that the device to be marketed is equivalent or better in safety and effectiveness to the legally marketed device.

In the FDA’s evaluation of the tests, it reviewed clinical data from a multisite study of more than 2,500 patients. This study evaluated the diagnostic accuracy of multiple commercially available nucleic acid amplification tests for detection of Neisseria gonorrhoeae and Chlamydia trachomatis from throat and rectal sites. The results of this study and other information reviewed by the FDA demonstrated that the two tests “are safe and effective for extragenital testing for chlamydia and gonorrhea,” according to the statement.

The data were collected through a cross-sectional study coordinated by the Antibacterial Resistance Leadership Group, which is funded and supported by the National Institute of Allergy and Infectious Diseases.

The FDA granted marketing clearance to Hologic and Cepheid for the Aptima Combo 2 Assay and the Xpert CT/NG, respectively.
 

[email protected]

The Food and Drug Administration has granted its first marketing clearance for extragenital diagnostic tests for chlamydia and gonorrhea.

The new tests, the Aptima Combo 2 Assay and Xpert CT/NG, use samples from the throat and rectum to test for chlamydia and gonorrhea, according to a statement from the FDA.

“It is best for patients if both [chlamydia and gonorrhea] are caught and treated right away, as significant complications can occur if left untreated,” noted Tim Stenzel, MD, in the statement.

“Today’s clearances provide a mechanism for more easily diagnosing these infections,” said Dr. Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health.

The two tests were reviewed through the premarket notification – or 510(k) – pathway, which seeks to demonstrate to the FDA that the device to be marketed is equivalent or better in safety and effectiveness to the legally marketed device.

In the FDA’s evaluation of the tests, it reviewed clinical data from a multisite study of more than 2,500 patients. This study evaluated the diagnostic accuracy of multiple commercially available nucleic acid amplification tests for detection of Neisseria gonorrhoeae and Chlamydia trachomatis from throat and rectal sites. The results of this study and other information reviewed by the FDA demonstrated that the two tests “are safe and effective for extragenital testing for chlamydia and gonorrhea,” according to the statement.

The data were collected through a cross-sectional study coordinated by the Antibacterial Resistance Leadership Group, which is funded and supported by the National Institute of Allergy and Infectious Diseases.

The FDA granted marketing clearance to Hologic and Cepheid for the Aptima Combo 2 Assay and the Xpert CT/NG, respectively.
 

[email protected]