The Journal of Pediatrics
Volume 153, Issue 3 , Pages 305-307, September 2008

Blame Vaccine Interference, Not Neonatal Immunization, for Suboptimal Responses after Neonatal Diphtheria, Tetanus, and Acellular Pertussis Immunization

  • Claire-Anne Siegrist, Prof

      Affiliations

    • Corresponding Author InformationReprint requests: Dr. Claire-Anne Siegrist, University of Geneva, Center for Vaccinolgy and Neonatal Immunology, CMU, 1, 1 Michel Servet, 1211 Geneva, Switzerland

WHO collaborating Center for Vaccinology and Neonatal Immunology, Department of Pediatrics and Pathology-Immunology, University of Geneva, Geneva, Switzerland

Article Outline

Abbreviations: aP, Acellular pertussis vaccine, D, Diphtheria toxoid, DTaP, Diphtheria and tetanus toxoid and acellular pertussis vaccine, FHA, Filamentous hemagglutinin, PT, Pertussis toxin, T, Tetanus toxoid

 

Current pertussis immunization strategies fail to protect neonates and infants too young to have been immunized; therefore specific preventive strategies are required. One possibility is to rely on maternal immunization for antibodies of maternal origin to confer transient pertussis immunity.1 Another strategy is to induce active immunity earlier in life through neonatal immunization. In this issue of The Journal, Halasa et al2 report the apparent failure of this approach. In their pilot study, 25 infants were given a dose of DTaP at birth, followed by routine infant immunization, including DTaP at 2, 4, 6, and 17 months. In contrast to their expectation, neonatal DTaP immunization reduced infant antibody responses to most vaccine antigens, including pertussis. At first glance, this report could condemn neonatal pertussis immunization strategies. However, these findings are in opposition to 3 recent demonstrations of successful neonatal immunization against pertussis. A 3-component acellular pertussis vaccine (aP) (Novartis Vaccines) given at birth to 45 infants subsequently immunized with DTaP at 3, 5, and 11 months was associated with significantly increased anti-PT, filamentous hemagglutinin (FHA), and pertactin (PRN) antibody levels after the first dose of DTaP.3 Another 3-component aP (GlaxoSmithKline) given to 60 neonates was associated with a significantly higher anti-PT, FHA, and PRN responses after the first infant dose.4 A single birth dose of the same aP vaccine was already immunogenic, as evidenced by significantly higher anti-PT antibody levels in 2-month-old infants.5 These 3 studies provide evidence that neonatal immunization may confer earlier antibody protection against pertussis, as it does against hepatitis B after neonatal immunization.

See related article, p 327

The study by Halasa et al2 therefore raises questions and suggests the following interpretation. The reduction of infant antibody responses did not result from the inhibitory influence of maternal antibodies, because antibodies were present at similarly low titers in both study groups.6 It does not reflect the failure of inducing a neonatal response. Although vaccine responses were not tested before 6 months of age, failure to elicit neonatal responses would have exerted no influence on infants' responses. The findings should not be mistaken for neonatal tolerance, as neonatally immunized infants did mount immune responses to all antigens, albeit at lower levels. Insufficient immunogenicity of the vaccines used in this study could be evoked, because vaccine responses in control infants were markedly lower than previously reported. However, adding an extra neonatal dose of a poorly immunogenic vaccine should have increased rather than reduced cumulative infant responses. Thus the conclusion should not be the failure of inducing neonatal immune responses to pertussis antigens, but rather the induction of vaccine interference.

Vaccine interference was previously defined as “a phenomenon that occurs when two or more vaccines are mixed together in the same formulation” (Wikipedia). Interference, however, is being recognized as a much broader issue, best defined as the modulation of vaccine responses that result from the concurrent or sequential administration of several distinct vaccines.7 Vaccine interference reflects vaccine-induced changes in cellular and molecular interactions that take place between vaccine-induced activated antigen-presenting cells, T-and B- lymphocytes. As an example of “positive interference,” vaccines such as BCG8 or whole-cell pertussis vaccines9 activate local antigen-presenting cells and enhance responses to distinct, but simultaneously presented vaccine antigens such as hepatitis B or Haemophilus influenza type b. In contrast, stimuli such as polysaccharide vaccines that force B-lymphocyte differentiation into antibody-secreting cells without generating memory cells deplete the B-cell pool, reducing subsequent responses to polysaccharide or conjugate vaccines.10 This mechanism is likely to be the basis of the blunting of anti-pertussis responses after neonatal administration of LPS-containing whole-cell pertussis vaccines, both in human beings and in mice.11 However, vaccine interferences mostly result from the modulation of CD4+ T-cell responses. In carrier-induced suppression, carrier-specific regulatory T-lymphocyte (T-regs, formerly called “suppressor cells”) interfere with anti-hapten responses when a conjugate vaccine is given to a host with preexisting anti-carrier immunity.12 In bystander T-lymphocyte–mediated interference, vaccine-induced T-lymphocytes alter responses to bystander antigens through changes in the Th1/Th2/Tregs balance. The exact patterns of T-lymphocyte responses that mediate vaccine interference remain to be identified. Interestingly, D- and CRM197-containing vaccines are, to date, the most frequent inducing agents of vaccine interference.13

Defining which mechanisms interfere with vaccine antibody responses after neonatal DTaP immunization may only be hypothesis driven, because cellular responses were not measured by Halasa et al.2 Such interferences were not observed in infants immunized neonatally with 2 other acellular pertussis vaccines.3, 4, 5 This could reflect differences in formulations, including a potential role of the adjuvant (aluminum hydroxide in GSK and Novartis vaccines, aluminum phosphate in Daptacel), known to affect pertussis vaccine immunogenicity and efficacy.14 However, the main distinction among the 4 studies is that neonatal immunization with aP elicited increased antibodies to pertussis antigens, whereas DTaP elicited decreased antibodies. The known contribution of diphtheria- (and not tetanus-) containing vaccines to the induction of vaccine interference,13 and the fact that neonatal DTaP affected anti-D but not anti-T responses, suggest that D-induced vaccine interference plays a major role. Regardless of the exact mechanisms at play, neonatal DTaP-induced interference was antigen specific, because it did not affect responses to tetanus toxoid or pertussis FHA. Neonatal DTaP exerted a transient influence on responses to CRM197-conjugates, presumably through changes in carrier-induced immunity. Finally, neonatal DTaP appears to have interfered with the induction of both antibody-secreting cells and memory B-lymphocytes to D, PT, PRN and fimbrial hemagglutinin, because differences between the experimental and control group persisted after subsequent doses of vaccines. Thus the study of Halasa et al2 does not condemn neonatal immunization against pertussis but suggests that neonatal administration of a DTaP vaccine triggers vaccine interference mechanisms.

Numerous questions nevertheless remain to be answered before neonatal immunization against pertussis could become an option. The main issue is to define the benefit of neonatal immunization in terms of protective efficacy. Evidence exists that even a single dose of DTaP in infancy may be sufficient to protect against severe disease and death. Should this be true also in neonates, neonatal immunization could be a life-saving strategy. In the absence of antibody correlates of protection against pertussis, demonstration of clinical efficacy will be challenging. In addition, it is now clear that any change in an infant immunization schedule may impact responses to other vaccines given concurrently or even subsequently. Whether this risk is increased after neonatal immunization is an important, interesting, and open question. The main contribution of the negative findings of Halasa et al2 may thus be to stress that immunization early in life is a complex issue requiring careful selection of vaccine formulations and immunization schedules, as well as appropriately designed comprehensive studies. It may be necessary to meet this challenge to improve vaccine protection in early life.

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References 

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PII: S0022-3476(08)00309-0

doi:10.1016/j.jpeds.2008.04.032

Refers to article:

  • Poor Immune Responses to a Birth Dose of Diphtheria, Tetanus, and Acellular Pertussis Vaccine , 28 April 2008

    Natasha B. Halasa, Alice O'Shea, Jian R. Shi, Bonnie J. LaFleur, Kathryn M. Edwards
    The Journal of Pediatrics September 2008 (Vol. 153, Issue 3, Pages 327-332.e1)

The Journal of Pediatrics
Volume 153, Issue 3 , Pages 305-307, September 2008

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