A call for new pertussis vaccines

VAIL, COLO. – Development of a better pertussis vaccine has emerged as a pressing need in light of persuasive evidence of waning immunity to current vaccines.

But can it be done? Can a new vaccine be created that provides enhanced efficacy and longer-lasting immunity without increasing reactogenicity?

"I think it can be done," Dr. Myron J. Levin said at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

©CDC

"The question you might ask is, can we do a better job than nature? After all, pertussis infection doesn’t cause lasting immunity, so could we do a better job than nature? I think so. And here’s an example: We know that antibody is protective against HPV [human papillomavirus], and that the HPV vaccine gives a much stronger antibody response, often by 100-fold, than does natural infection with HPV," observed Dr. Levin, who led development of the shingles vaccine.

Convincing evidence of waning immunity to the current five-dose diphtheria, tetanus, and acellular pertussis (DTaP) vaccine series completed before age 7 years in the United States comes from research conducted at the Kaiser Permanente Vaccine Study Center in Oakland, Calif. The investigators analyzed the large California pertussis outbreak of 2010. Their case-control study showed that the protection provided by the DTaP vaccine was short-lived, such that each year after completing the fifth dose the likelihood of developing PCR-proven pertussis climbed by an average of 42% (N. Engl. J. Med. 2012;367:1012-9).

Thus, they calculated that if the initial effectiveness of DTaP was 90%, it would drop to a mere 42% 5 years after the fifth and final dose. In addition, there is a strong argument that the original estimate of the vaccine’s efficacy of about 85% was inflated due to the case definition used. The efficacy rate after 5 years becomes disturbingly low if the actual efficacy rate was roughly 7%, as many now believe, noted Dr. Levin, professor of pediatrics and medicine at the University of Colorado, Denver.

The whole-cell pertussis vaccines were clearly more effective than the DTaP, which began replacing them in the early 1990s. In another Kaiser Permanente study that zeroed in on the transition period between the use of whole-cell pertussis vaccine and DTaP, patients who contracted PCR-confirmed pertussis did so an average of 14.7 years after receiving their last dose in the series if they received one or more doses of whole-cell vaccine compared with a mere 5.6 years after the last dose if they got the all-DTaP series.

The national switch to DTaP was carried out because the vaccine has fewer adverse effects than does the whole-cell pertussis vaccine. Components of whole-cell vaccines, including lipopolysaccharides and internal proteins, were important in signaling the innate immune system to shape a more robust response. Unfortunately, these whole-cell vaccine components also trigger unwanted reactogenic local and systemic effects.

"Whenever a vaccine is cleaned up to decrease side effects, there is a great likelihood that the efficacy will be affected. This is almost certainly the case with acellular pertussis, and probably with the split-product flu vaccines as well. I would say we need to learn why the whole-cell pertussis vaccine was so effective – which component was most important in directing the immune response – and see if we can separate that from the side effects. This is a research issue," said Dr. Levin.

Possible ways to create a better DTaP vaccine might involve incorporating a detoxified lipopolysaccharide or adding additional adjuvants to increase the innate immune response to the pertussis antigen.

Vaccine development takes time. In the interim, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has taken steps to deal with the nation’s worsening pertussis epidemic outbreak. Because the herd protection effect is probably low, a "cocooning" strategy has been adopted. This involves targeted immunization of pregnant women and all close contacts of their babies during the first year of life, when pertussis has its highest morbidity and mortality. In addition, an adolescent dose of pertussis vaccine has been introduced. And consideration is being given to the possibility of universal once-per-decade booster doses in adults, but this has thus far been rejected as not being cost-effective.

Dr. Levin reported receiving honoraria from Novartis and GlaxoSmithKline and royalties as well as honoraria from Merck, Sharpe, and Dohme.

[email protected]

VAIL, COLO. – Development of a better pertussis vaccine has emerged as a pressing need in light of persuasive evidence of waning immunity to current vaccines.

But can it be done? Can a new vaccine be created that provides enhanced efficacy and longer-lasting immunity without increasing reactogenicity?

"I think it can be done," Dr. Myron J. Levin said at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

©CDC

"The question you might ask is, can we do a better job than nature? After all, pertussis infection doesn’t cause lasting immunity, so could we do a better job than nature? I think so. And here’s an example: We know that antibody is protective against HPV [human papillomavirus], and that the HPV vaccine gives a much stronger antibody response, often by 100-fold, than does natural infection with HPV," observed Dr. Levin, who led development of the shingles vaccine.

Convincing evidence of waning immunity to the current five-dose diphtheria, tetanus, and acellular pertussis (DTaP) vaccine series completed before age 7 years in the United States comes from research conducted at the Kaiser Permanente Vaccine Study Center in Oakland, Calif. The investigators analyzed the large California pertussis outbreak of 2010. Their case-control study showed that the protection provided by the DTaP vaccine was short-lived, such that each year after completing the fifth dose the likelihood of developing PCR-proven pertussis climbed by an average of 42% (N. Engl. J. Med. 2012;367:1012-9).

Thus, they calculated that if the initial effectiveness of DTaP was 90%, it would drop to a mere 42% 5 years after the fifth and final dose. In addition, there is a strong argument that the original estimate of the vaccine’s efficacy of about 85% was inflated due to the case definition used. The efficacy rate after 5 years becomes disturbingly low if the actual efficacy rate was roughly 7%, as many now believe, noted Dr. Levin, professor of pediatrics and medicine at the University of Colorado, Denver.

The whole-cell pertussis vaccines were clearly more effective than the DTaP, which began replacing them in the early 1990s. In another Kaiser Permanente study that zeroed in on the transition period between the use of whole-cell pertussis vaccine and DTaP, patients who contracted PCR-confirmed pertussis did so an average of 14.7 years after receiving their last dose in the series if they received one or more doses of whole-cell vaccine compared with a mere 5.6 years after the last dose if they got the all-DTaP series.

The national switch to DTaP was carried out because the vaccine has fewer adverse effects than does the whole-cell pertussis vaccine. Components of whole-cell vaccines, including lipopolysaccharides and internal proteins, were important in signaling the innate immune system to shape a more robust response. Unfortunately, these whole-cell vaccine components also trigger unwanted reactogenic local and systemic effects.

"Whenever a vaccine is cleaned up to decrease side effects, there is a great likelihood that the efficacy will be affected. This is almost certainly the case with acellular pertussis, and probably with the split-product flu vaccines as well. I would say we need to learn why the whole-cell pertussis vaccine was so effective – which component was most important in directing the immune response – and see if we can separate that from the side effects. This is a research issue," said Dr. Levin.

Possible ways to create a better DTaP vaccine might involve incorporating a detoxified lipopolysaccharide or adding additional adjuvants to increase the innate immune response to the pertussis antigen.

Vaccine development takes time. In the interim, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has taken steps to deal with the nation’s worsening pertussis epidemic outbreak. Because the herd protection effect is probably low, a "cocooning" strategy has been adopted. This involves targeted immunization of pregnant women and all close contacts of their babies during the first year of life, when pertussis has its highest morbidity and mortality. In addition, an adolescent dose of pertussis vaccine has been introduced. And consideration is being given to the possibility of universal once-per-decade booster doses in adults, but this has thus far been rejected as not being cost-effective.

Dr. Levin reported receiving honoraria from Novartis and GlaxoSmithKline and royalties as well as honoraria from Merck, Sharpe, and Dohme.

[email protected]

VAIL, COLO. – Development of a better pertussis vaccine has emerged as a pressing need in light of persuasive evidence of waning immunity to current vaccines.

But can it be done? Can a new vaccine be created that provides enhanced efficacy and longer-lasting immunity without increasing reactogenicity?

"I think it can be done," Dr. Myron J. Levin said at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

©CDC

"The question you might ask is, can we do a better job than nature? After all, pertussis infection doesn’t cause lasting immunity, so could we do a better job than nature? I think so. And here’s an example: We know that antibody is protective against HPV [human papillomavirus], and that the HPV vaccine gives a much stronger antibody response, often by 100-fold, than does natural infection with HPV," observed Dr. Levin, who led development of the shingles vaccine.

Convincing evidence of waning immunity to the current five-dose diphtheria, tetanus, and acellular pertussis (DTaP) vaccine series completed before age 7 years in the United States comes from research conducted at the Kaiser Permanente Vaccine Study Center in Oakland, Calif. The investigators analyzed the large California pertussis outbreak of 2010. Their case-control study showed that the protection provided by the DTaP vaccine was short-lived, such that each year after completing the fifth dose the likelihood of developing PCR-proven pertussis climbed by an average of 42% (N. Engl. J. Med. 2012;367:1012-9).

Thus, they calculated that if the initial effectiveness of DTaP was 90%, it would drop to a mere 42% 5 years after the fifth and final dose. In addition, there is a strong argument that the original estimate of the vaccine’s efficacy of about 85% was inflated due to the case definition used. The efficacy rate after 5 years becomes disturbingly low if the actual efficacy rate was roughly 7%, as many now believe, noted Dr. Levin, professor of pediatrics and medicine at the University of Colorado, Denver.

The whole-cell pertussis vaccines were clearly more effective than the DTaP, which began replacing them in the early 1990s. In another Kaiser Permanente study that zeroed in on the transition period between the use of whole-cell pertussis vaccine and DTaP, patients who contracted PCR-confirmed pertussis did so an average of 14.7 years after receiving their last dose in the series if they received one or more doses of whole-cell vaccine compared with a mere 5.6 years after the last dose if they got the all-DTaP series.

The national switch to DTaP was carried out because the vaccine has fewer adverse effects than does the whole-cell pertussis vaccine. Components of whole-cell vaccines, including lipopolysaccharides and internal proteins, were important in signaling the innate immune system to shape a more robust response. Unfortunately, these whole-cell vaccine components also trigger unwanted reactogenic local and systemic effects.

"Whenever a vaccine is cleaned up to decrease side effects, there is a great likelihood that the efficacy will be affected. This is almost certainly the case with acellular pertussis, and probably with the split-product flu vaccines as well. I would say we need to learn why the whole-cell pertussis vaccine was so effective – which component was most important in directing the immune response – and see if we can separate that from the side effects. This is a research issue," said Dr. Levin.

Possible ways to create a better DTaP vaccine might involve incorporating a detoxified lipopolysaccharide or adding additional adjuvants to increase the innate immune response to the pertussis antigen.

Vaccine development takes time. In the interim, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention has taken steps to deal with the nation’s worsening pertussis epidemic outbreak. Because the herd protection effect is probably low, a "cocooning" strategy has been adopted. This involves targeted immunization of pregnant women and all close contacts of their babies during the first year of life, when pertussis has its highest morbidity and mortality. In addition, an adolescent dose of pertussis vaccine has been introduced. And consideration is being given to the possibility of universal once-per-decade booster doses in adults, but this has thus far been rejected as not being cost-effective.

Dr. Levin reported receiving honoraria from Novartis and GlaxoSmithKline and royalties as well as honoraria from Merck, Sharpe, and Dohme.

[email protected]