Why so many pertussis outbreaks despite acellular pertussis vaccine? A call to action

There has been a justified re-examination of acellular pertussis vaccine (aP)^1,2 in light of the multiple large outbreaks of pertussis since 2000, particularly the two large California outbreaks in 2010 and 2014.

Lessons learned: aP protection is less durable than originally thought, and much pertussis is not in infants, but in the school-age and adolescent populations.

aP appears to produce reasonable protection (approximately 84% overall) for infants and preschool children, plus a much improved adverse effect profile, compared with whole cell pertussis vaccine (WCP), which provided approximately 94% protection.¹ This 10% difference in aP versus WCP, however, means that herd immunity is more difficult to attain. The accepted pertussis immunization rate needed to provide herd immunity is 92%-94%. Because our current tools (DTaP and Tdap) provide only 84% protection at least in infants and preschoolers, even 100% uptake may leave us 6% to 8% short of the threshold for complete herd immunity.

The California outbreak data from school-age and teenage populations show protection rates drop each year post aP booster. That means that by the fourth year after the last dose, protection is less than 10%. So despite a Tdap dose at 11- to 12-years-of-age, protection gaps occur in 8-to 10-year-olds and 14- to 18-year-olds. These vulnerable periods in older children add to aP’s 84% vs. WCP’s 94% protection for those greater than 3 years of age, explaining more frequent pertussis outbreaks as the pool of WCP-immunized children among older populations decreased.

But before we place all blame on switching to aP, consider that we can now confirm more pertussis infections with molecular assays than was possible with culture and fluorescent assay testing in the WCP era. So improved testing sensitivity means more reports of minimally symptomatic cases that may have been missed before. So WCP, if still used today, might not show 94% protection either.

Additionally, aPs rely heavily on pertactin as a target antigen,³ likely less than WCP, given that WCP contained all pertussis antigens rather than just the 3-5 purified antigens in aPs. So the emergence of pertactin-altered pertussis strains could disproportionately affect protection from aP, compared with WCP.

There seem to be no quick fixes to preventing outbreaks using aPs as our vaccine. One suggestion by the authors of the California outbreak report is to use aP mostly to terminate outbreaks rather than routinely in late childhood. My concern is that if we do not continue routine use in 4-to 6-year-olds, 10-to 11-year-olds, and in early adulthood, the vulnerable proportion of the population during outbreaks would be larger, making outbreaks more difficult to terminate. So continuing to produce some protection, albeit short-lived, with current schedules of aP vaccines seems important.

Also remember that T cells, particularly TH 17 pertussis-specific cells, may be as important as pertussis antibody. Therefore, crafting pertussis vaccines that yield improved antibody plus T cell responses is the current goal. Disease and WCP seem to elicit more T-17 response than aP. One method to craft a better vaccine is to use antigen blends that differ from those in the current vaccines, such as antigens derived from circulating pertussis strains instead of the standard laboratory strain. Another option is to use current antigens but with more potent adjuvants. Such vaccines are likely 5 years away.

But we need to have reasonable expectations for pertussis vaccines. Pertussis infection begins in respiratory epithelium. Many of the most obvious signs and symptoms are due to destruction of ciliated respiratory epithelium plus increased tenacity/volume of secretions. Can a parenterally administered vaccine that induces mostly serum antibody protect against infection of epithelium where antibody concentrations are likely 10% or less than in serum? The short answer is – likely not. We should expect neither aP nor WCP to consistently protect against pertussis infection, but it does seem reasonable to expect aP to reduce disease severity. Preventing infections awaits a vaccine that induces surface IgA. Mucosally administered vaccines produce surface IgA – for example, rotavirus vaccine – but no mucosal pertussis vaccine appears imminent.

A key question is whether our most vulnerable populations, young children, have increased morbidity and mortality. Data from the California suggest an increase but mostly in infants under 6 months of age, the group not old enough to benefit from even the most effective of infant vaccines. Protecting young infants depends on vaccine administered prenatally to mothers. The over-representation of the Hispanic infants among fatalities shows a population on which to focus with maternal immunization. Hopefully, the recent universal TdaP recommendation in pregnancy will help when maternal immunization is higher than current approximately 50% rates.⁴

Despite the problems, it seems clear that we must continue to use current aP vaccines according to the current schedules, attempting to get as close to 100% uptake as possible. While the current, nearly 10% unimmunized rates add to the likelihood that we are losing complete herd immunity, partial herd immunity is better than no herd immunity.

Expectations: There will be ongoing outbreaks. Continue to be alert for signs of pertussis. They are often less obvious in older patients, and may be as subtle as more than 2 weeks of persistent cough. During outbreaks, we may be called upon to give aP doses at intervals shorter than the usual schedule.

Our responsibility: Do not become discouraged or lose enthusiasm for aP, but explain to parents that because aP is less reactogenic, it produces less protection and is less durable, particularly in school-age children. But please emphasize that modest protection is best in the youngest and modest protection of older children is better than none. Emphasize that the adverse effect profile of current aPs puts the harm/benefit balance heavily in favor of aP.

Bottom line: We can hopefully do better than the current 88% to 92% rate of aP vaccine uptake. We need to get as close to 100% uptake as possible until new vaccines or new strategies become available.

1. Clin Infect Dis. 2016 Feb 7; doi: 10.1093/cid/ciw051.

2. Pediatrics. 2016 Feb 5; doi: 10.1542/peds.2015-3326.

3. Expert Rev Vaccines. 2007 Feb;6(1):47-56.

4. Vaccine. 2016 Feb 10;34(7):968-73.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He disclosed that his institution received grant support for a study on hexavalent infant vaccine containing pertussis from GlaxoSmithKline, and he was the local primary investigator.*

*Correction, 2/17/2016: An earlier version of this article incompletely stated Dr. Harrison's disclosure information.

There has been a justified re-examination of acellular pertussis vaccine (aP)^1,2 in light of the multiple large outbreaks of pertussis since 2000, particularly the two large California outbreaks in 2010 and 2014.

Lessons learned: aP protection is less durable than originally thought, and much pertussis is not in infants, but in the school-age and adolescent populations.

aP appears to produce reasonable protection (approximately 84% overall) for infants and preschool children, plus a much improved adverse effect profile, compared with whole cell pertussis vaccine (WCP), which provided approximately 94% protection.¹ This 10% difference in aP versus WCP, however, means that herd immunity is more difficult to attain. The accepted pertussis immunization rate needed to provide herd immunity is 92%-94%. Because our current tools (DTaP and Tdap) provide only 84% protection at least in infants and preschoolers, even 100% uptake may leave us 6% to 8% short of the threshold for complete herd immunity.

The California outbreak data from school-age and teenage populations show protection rates drop each year post aP booster. That means that by the fourth year after the last dose, protection is less than 10%. So despite a Tdap dose at 11- to 12-years-of-age, protection gaps occur in 8-to 10-year-olds and 14- to 18-year-olds. These vulnerable periods in older children add to aP’s 84% vs. WCP’s 94% protection for those greater than 3 years of age, explaining more frequent pertussis outbreaks as the pool of WCP-immunized children among older populations decreased.

But before we place all blame on switching to aP, consider that we can now confirm more pertussis infections with molecular assays than was possible with culture and fluorescent assay testing in the WCP era. So improved testing sensitivity means more reports of minimally symptomatic cases that may have been missed before. So WCP, if still used today, might not show 94% protection either.

Additionally, aPs rely heavily on pertactin as a target antigen,³ likely less than WCP, given that WCP contained all pertussis antigens rather than just the 3-5 purified antigens in aPs. So the emergence of pertactin-altered pertussis strains could disproportionately affect protection from aP, compared with WCP.

There seem to be no quick fixes to preventing outbreaks using aPs as our vaccine. One suggestion by the authors of the California outbreak report is to use aP mostly to terminate outbreaks rather than routinely in late childhood. My concern is that if we do not continue routine use in 4-to 6-year-olds, 10-to 11-year-olds, and in early adulthood, the vulnerable proportion of the population during outbreaks would be larger, making outbreaks more difficult to terminate. So continuing to produce some protection, albeit short-lived, with current schedules of aP vaccines seems important.

Also remember that T cells, particularly TH 17 pertussis-specific cells, may be as important as pertussis antibody. Therefore, crafting pertussis vaccines that yield improved antibody plus T cell responses is the current goal. Disease and WCP seem to elicit more T-17 response than aP. One method to craft a better vaccine is to use antigen blends that differ from those in the current vaccines, such as antigens derived from circulating pertussis strains instead of the standard laboratory strain. Another option is to use current antigens but with more potent adjuvants. Such vaccines are likely 5 years away.

But we need to have reasonable expectations for pertussis vaccines. Pertussis infection begins in respiratory epithelium. Many of the most obvious signs and symptoms are due to destruction of ciliated respiratory epithelium plus increased tenacity/volume of secretions. Can a parenterally administered vaccine that induces mostly serum antibody protect against infection of epithelium where antibody concentrations are likely 10% or less than in serum? The short answer is – likely not. We should expect neither aP nor WCP to consistently protect against pertussis infection, but it does seem reasonable to expect aP to reduce disease severity. Preventing infections awaits a vaccine that induces surface IgA. Mucosally administered vaccines produce surface IgA – for example, rotavirus vaccine – but no mucosal pertussis vaccine appears imminent.

A key question is whether our most vulnerable populations, young children, have increased morbidity and mortality. Data from the California suggest an increase but mostly in infants under 6 months of age, the group not old enough to benefit from even the most effective of infant vaccines. Protecting young infants depends on vaccine administered prenatally to mothers. The over-representation of the Hispanic infants among fatalities shows a population on which to focus with maternal immunization. Hopefully, the recent universal TdaP recommendation in pregnancy will help when maternal immunization is higher than current approximately 50% rates.⁴

Despite the problems, it seems clear that we must continue to use current aP vaccines according to the current schedules, attempting to get as close to 100% uptake as possible. While the current, nearly 10% unimmunized rates add to the likelihood that we are losing complete herd immunity, partial herd immunity is better than no herd immunity.

Expectations: There will be ongoing outbreaks. Continue to be alert for signs of pertussis. They are often less obvious in older patients, and may be as subtle as more than 2 weeks of persistent cough. During outbreaks, we may be called upon to give aP doses at intervals shorter than the usual schedule.

Our responsibility: Do not become discouraged or lose enthusiasm for aP, but explain to parents that because aP is less reactogenic, it produces less protection and is less durable, particularly in school-age children. But please emphasize that modest protection is best in the youngest and modest protection of older children is better than none. Emphasize that the adverse effect profile of current aPs puts the harm/benefit balance heavily in favor of aP.

Bottom line: We can hopefully do better than the current 88% to 92% rate of aP vaccine uptake. We need to get as close to 100% uptake as possible until new vaccines or new strategies become available.

1. Clin Infect Dis. 2016 Feb 7; doi: 10.1093/cid/ciw051.

2. Pediatrics. 2016 Feb 5; doi: 10.1542/peds.2015-3326.

3. Expert Rev Vaccines. 2007 Feb;6(1):47-56.

4. Vaccine. 2016 Feb 10;34(7):968-73.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He disclosed that his institution received grant support for a study on hexavalent infant vaccine containing pertussis from GlaxoSmithKline, and he was the local primary investigator.*

*Correction, 2/17/2016: An earlier version of this article incompletely stated Dr. Harrison's disclosure information.

There has been a justified re-examination of acellular pertussis vaccine (aP)^1,2 in light of the multiple large outbreaks of pertussis since 2000, particularly the two large California outbreaks in 2010 and 2014.

Lessons learned: aP protection is less durable than originally thought, and much pertussis is not in infants, but in the school-age and adolescent populations.

aP appears to produce reasonable protection (approximately 84% overall) for infants and preschool children, plus a much improved adverse effect profile, compared with whole cell pertussis vaccine (WCP), which provided approximately 94% protection.¹ This 10% difference in aP versus WCP, however, means that herd immunity is more difficult to attain. The accepted pertussis immunization rate needed to provide herd immunity is 92%-94%. Because our current tools (DTaP and Tdap) provide only 84% protection at least in infants and preschoolers, even 100% uptake may leave us 6% to 8% short of the threshold for complete herd immunity.

The California outbreak data from school-age and teenage populations show protection rates drop each year post aP booster. That means that by the fourth year after the last dose, protection is less than 10%. So despite a Tdap dose at 11- to 12-years-of-age, protection gaps occur in 8-to 10-year-olds and 14- to 18-year-olds. These vulnerable periods in older children add to aP’s 84% vs. WCP’s 94% protection for those greater than 3 years of age, explaining more frequent pertussis outbreaks as the pool of WCP-immunized children among older populations decreased.

But before we place all blame on switching to aP, consider that we can now confirm more pertussis infections with molecular assays than was possible with culture and fluorescent assay testing in the WCP era. So improved testing sensitivity means more reports of minimally symptomatic cases that may have been missed before. So WCP, if still used today, might not show 94% protection either.

Additionally, aPs rely heavily on pertactin as a target antigen,³ likely less than WCP, given that WCP contained all pertussis antigens rather than just the 3-5 purified antigens in aPs. So the emergence of pertactin-altered pertussis strains could disproportionately affect protection from aP, compared with WCP.

There seem to be no quick fixes to preventing outbreaks using aPs as our vaccine. One suggestion by the authors of the California outbreak report is to use aP mostly to terminate outbreaks rather than routinely in late childhood. My concern is that if we do not continue routine use in 4-to 6-year-olds, 10-to 11-year-olds, and in early adulthood, the vulnerable proportion of the population during outbreaks would be larger, making outbreaks more difficult to terminate. So continuing to produce some protection, albeit short-lived, with current schedules of aP vaccines seems important.

Also remember that T cells, particularly TH 17 pertussis-specific cells, may be as important as pertussis antibody. Therefore, crafting pertussis vaccines that yield improved antibody plus T cell responses is the current goal. Disease and WCP seem to elicit more T-17 response than aP. One method to craft a better vaccine is to use antigen blends that differ from those in the current vaccines, such as antigens derived from circulating pertussis strains instead of the standard laboratory strain. Another option is to use current antigens but with more potent adjuvants. Such vaccines are likely 5 years away.

But we need to have reasonable expectations for pertussis vaccines. Pertussis infection begins in respiratory epithelium. Many of the most obvious signs and symptoms are due to destruction of ciliated respiratory epithelium plus increased tenacity/volume of secretions. Can a parenterally administered vaccine that induces mostly serum antibody protect against infection of epithelium where antibody concentrations are likely 10% or less than in serum? The short answer is – likely not. We should expect neither aP nor WCP to consistently protect against pertussis infection, but it does seem reasonable to expect aP to reduce disease severity. Preventing infections awaits a vaccine that induces surface IgA. Mucosally administered vaccines produce surface IgA – for example, rotavirus vaccine – but no mucosal pertussis vaccine appears imminent.

A key question is whether our most vulnerable populations, young children, have increased morbidity and mortality. Data from the California suggest an increase but mostly in infants under 6 months of age, the group not old enough to benefit from even the most effective of infant vaccines. Protecting young infants depends on vaccine administered prenatally to mothers. The over-representation of the Hispanic infants among fatalities shows a population on which to focus with maternal immunization. Hopefully, the recent universal TdaP recommendation in pregnancy will help when maternal immunization is higher than current approximately 50% rates.⁴

Despite the problems, it seems clear that we must continue to use current aP vaccines according to the current schedules, attempting to get as close to 100% uptake as possible. While the current, nearly 10% unimmunized rates add to the likelihood that we are losing complete herd immunity, partial herd immunity is better than no herd immunity.

Expectations: There will be ongoing outbreaks. Continue to be alert for signs of pertussis. They are often less obvious in older patients, and may be as subtle as more than 2 weeks of persistent cough. During outbreaks, we may be called upon to give aP doses at intervals shorter than the usual schedule.

Our responsibility: Do not become discouraged or lose enthusiasm for aP, but explain to parents that because aP is less reactogenic, it produces less protection and is less durable, particularly in school-age children. But please emphasize that modest protection is best in the youngest and modest protection of older children is better than none. Emphasize that the adverse effect profile of current aPs puts the harm/benefit balance heavily in favor of aP.

Bottom line: We can hopefully do better than the current 88% to 92% rate of aP vaccine uptake. We need to get as close to 100% uptake as possible until new vaccines or new strategies become available.

1. Clin Infect Dis. 2016 Feb 7; doi: 10.1093/cid/ciw051.

2. Pediatrics. 2016 Feb 5; doi: 10.1542/peds.2015-3326.

3. Expert Rev Vaccines. 2007 Feb;6(1):47-56.

4. Vaccine. 2016 Feb 10;34(7):968-73.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He disclosed that his institution received grant support for a study on hexavalent infant vaccine containing pertussis from GlaxoSmithKline, and he was the local primary investigator.*

*Correction, 2/17/2016: An earlier version of this article incompletely stated Dr. Harrison's disclosure information.