Pertussis is a major public health concern. In 2014, 24 million cases and 160 000 deaths from pertussis in children <5 years were estimated worldwide, with nearly one-third of the cases occurring in Africa.1 Vaccination with an acellular pertussis (aP)–containing vaccine in pregnancy prevents severe pertussis in young infants and has been recommended in an increasing number of high-income countries (HICs). We have recently discussed optimal strategies for vaccination in pregnancy to maximize protection against infections in infancy.2 However, pertussis vaccination in pregnancy reduces infants’ primary immune responses to diphtheria-tetanus-acellular pertussis (DTaP) vaccines, leading to lower antibody levels to some pertussis antigens, when compared with infants of unvaccinated mothers.3 This is termed “interference” and has been shown primarily in studies from HICs that used DTaP formulations for infant immunization, but its clinical implications are unknown. Fewer data are available on the potential interference with diphtheria, tetanus, and whole-cell pertussis (DTwP) vaccines for infant immunization, the vaccines used almost exclusively in low- and middle-income countries (LMICs).
An earlier study that we conducted in the United States revealed interference with DTwP vaccines, but not with DTaP vaccines, in infants with higher maternally derived antibody levels before primary vaccination.4 In a recent study conducted in Pakistan, the authors found no correlation between preexisting anti-pertussis antibody levels at delivery and infants’ anti-pertussis antibody levels after primary vaccination with DTwP vaccines.5 However, women in these 2 studies did not receive pertussis vaccines during pregnancy, and their anti-pertussis antibody levels were lower than those measured after maternal immunization. In another recent study, Thai infants who were born to aP-vaccinated mothers and vaccinated with DTwP had lower postprimary vaccination anti-pertussis antibody levels than infants who were born to aP-vaccinated women and vaccinated with DTaP.6 Altogether, these studies suggest that although low preexisting, maternally derived anti-pertussis antibody levels do not interfere with infants’ immune responses to vaccination with DTwP,5 high maternally derived anti-pertussis antibody levels that result from maternal immunization do interfere with infants’ immune responses to DTwP vaccines.6
Significance of Interference With Pertussis Vaccination From HICs and LMICs Perspectives
A Growing Population of Infants Born to aP-Vaccinated Mothers
Vaccination with aP-containing vaccine in pregnancy has been implemented in an increasing number of HICs and countries where infant primary vaccination with DTwP is routinely used (eg, Argentina and Brazil). The Technical Advisory Group of the Pan American Health Organization recently endorsed the World Health Organization (WHO) Strategic Advisory Group of Experts recommendation for aP vaccination in each pregnancy in Latin America, a setting where DTwP vaccines are routinely given to infants. Thus, if maternal pertussis vaccination strategy becomes widely implemented in these and other LMICs, a growing population of infants born to aP-vaccinated women will receive DTwP vaccines and could potentially be impacted by interference.
Clinical Significance of Interference Is More Challenging to Establish in LMICs than HICs
The clinical significance of interference with DTaP vaccination in infancy in HICs is being actively evaluated by using existing well-established pertussis disease surveillance systems. Current data from the United States do not suggest that interference poses a clinical problem. However, the clinical significance of interference with DTwP vaccination would likely be more difficult to determine in LMICs because of the lack of comprehensive surveillance systems. Moreover, the interpretation of short-term epidemiological data on interference is challenging in both HICs and LMICs because of the nature of pertussis disease epidemiology, characterized by cyclical peaks and 3 to 5 years of interepidemic periods. With these challenges, immunogenicity data derived from trials would likely be the only available tool to guide recommendations in LMICs with less well-established surveillance systems. This is further complicated by the lack of serological correlates of protection against pertussis disease.
Mitigating the Effect of Interference Is More Challenging in LMICs than HICs
The recent serological data indicating that DTwP vaccination of infants born to aP-vaccinated mothers is associated with more interference compared with vaccination with DTaP may justify the change from DTwP to DTaP formulations in LMICs with maternal pertussis vaccination programs. However, the WHO recommended in 2015 that national programs administering DTwP vaccines should continue to use these formulations for primary vaccination.7 This statement was made before widespread implementation of maternal pertussis immunization programs. The switch from DTwP to DTaP vaccines for primary infants’ vaccination is supported by the WHO if the inclusion of maternal pertussis vaccination programs could be ensured and sustained.7 Current DTaP vaccines are more costly than DTwP vaccines, and waning immunity to available DTaP vaccine formulations represents an additional challenge.7 New, more immunogenic DTaP vaccines, designed to overcome these challenges, have the potential to induce longer-lasting pertussis immunity.8
Another option to mitigate the impact of interference would be to delay the initiation of pertussis primary vaccination in infants born to pertussis-vaccinated mothers. This approach has been successfully used to circumvent the effect of maternal antibodies on immune response to measles and influenza vaccines and is being evaluated for pertussis in some high-income settings (eg, Netherlands). However, WHO recommendations, pertinent more to LMICs, emphasize that infants should receive a 3-dose pertussis primary vaccination series commencing as early as 6 weeks of age, with subsequent doses given 4 to 8 weeks apart (at 10–14 and 14–18 weeks).7 Taken together, delaying primary vaccination in LMICs would likely be complicated by WHO recommendations that encourage countries to achieve early and timely vaccination, with the first dose of a pertussis vaccine given between 6 and 8 weeks of age.7 In addition, other vaccine antigens must be administered at these early times and are often given in combination with pertussis antigens (eg, hepatitis B, Haemophilus influenzae type b). Because most of these vaccine-preventable diseases are highly relevant to LMICs, delaying primary immunization would be problematic.
Additional mitigation approaches could be investigated. An earlier study we conducted revealed that a DTaP vaccine containing genetically modified pertussis toxin was more immunogenic than a vaccine containing chemically detoxified pertussis toxin in infants,9 and these observations were recently confirmed in adolescents.8 Other new vaccine candidates include live-attenuated vaccines and vaccines based on the outer membrane vesicle. Furthermore, investigating the mechanism of interference might shed light on new approaches to mitigate its effect.
Assessing the Impact of Interference on Pertussis Burden
Continued surveillance for the impact of interference in HICs, such as the United States, should continue, and the data are reassuring at this time. LMICs implementing maternal immunization should enhance surveillance for pertussis disease to detect whether interference is clinically significant. In addition, data from middle-income countries with pertussis surveillance systems (eg, Argentina) could inform low-income countries lacking such infrastructure. The challenge in using immunogenicity data to assess interference should stimulate studies aimed at further assessing pertussis correlates of protection, against which results of trials can be compared.
What Pediatricians Should Know About Maternal Immunization
Pediatricians should know that pertussis vaccination in every pregnancy is currently the recommended strategy to prevent severe pertussis in young infants in HICs, including the United States. This strategy appears to be highly successful in reducing pertussis morbidity and mortality in young infants. Whether it will be as successful in countries where infants are given DTwP will need to be carefully assessed. Providers in both HICs and LMICs should investigate infants with symptoms suggestive of pertussis disease, even if the disease is mild or the symptoms are nonclassic. Pertussis-confirmed cases should be reported, along with maternal immunization history, to help determine if interference has clinical significance.
Drs Abu-Raya and Edwards conceptualized and drafted the initial manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Edwards serves as an advisor for Bionet and Merck and on data safety and monitoring boards for Sanofi, X4 Pharmaceuticals, Seqirus, Moderna, and Pfizer; and Dr Abu-Raya has indicated he has no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: Dr Abu-Raya is supported by the Canadian Health and Research Institute Vanier Canada Graduate Scholarship. Dr Edwards serves as an advisor for Bionet and Merck and on data safety and monitoring boards for Sanofi, X4 Pharmaceuticals, Seqirus, Moderna, and Pfizer.