Immunological studies in animal models 

 The animal studies of NSEs will focus on exploring the negative immunological effects of inactivated vaccines and to further explore the most promising immunological findings from the RCTs. We are planning studies together with Mahon (Ireland), who has a murine model to study the effect of pertussis vaccine on ovalbumin responses43, and Ross (US), who has a murine model of neonatal S. pneumoniae infection. Using these models we will investigate whether the whole cell pertussis component is the main agent of the negative NSEs of DTP. This will be done by comparing its effects with the effects of the acellular pertussis component, the individual vaccine components, the complete DTP formulation, and the alum-based adjuvant alone. Additionally we will test the pentavalent vaccine, which is currently the recommended vaccine in the EPI schedules in Africa. We will furthermore study the effect of the combination and sequence of DTP and BCG.

Conclusion: Implausible but repeatable

 Our research program of RCTs and observational studies of the real-life effects of vaccines and micronutrients has reached the stage where we can focus on the beneficial effects of live vaccines and on preventing the negative effects of DTP and DTP+VAS, because these unexpected effects have been repeatable. The immunological studies are in an earlier phase, but providing interesting observations; e.g. the strong sex-differential immunological effects of receiving MV alone or DTP+MV31. The ongoing RCTs, observational and immunological studies will define the next round of studies within CVIVA (Figure 1).

The NSEs are far larger than the expected effects of prevention. Though the teams’ research is gaining greater credibility as evidenced by many editorials59-64, current science mainly looks for specific effects and many researchers have labeled the NSEs “biologically implausible”. However, the unexpected NSEs are repeatable and hold the potential for major reductions in child mortality in low-income countries as well as for new insights. A grant from the DNRF could significantly accelerate the process towards a paradigm shift.