On Robert F Kennedy Jr's comments on our studies of diphtheria-tetanus-pertussis vaccine

Many people have alerted me to the fact that Robert F Kennedy Jr has been mentioning our group’s studies on the whole-cell diphtheria-tetanus-pertussis (DTP) vaccine used in Africa. They asked me if the story is true. Allow me to present the story from our perspective. In brief, some details are wrong, but the overall message - that we discovered a serious safety signal in relation to DTP vaccine for females - is correct.

Our research group, the Bandim Health Project (BHP), was established in 1978. It is not a goverment group. Apart from the last five years, where we have received a bit of core funding from our new “host”, the Danish state University of Southern Denmark, we are only funded by grants for specific research projects. We apply for these grants from governmental and private foundations. The funders have no role in the studies. Hence, we are an independent research group with no conflicts of interest.

The BHP runs a field station in Guinea-Bissau in Africa. Here, child mortality has historically been extremely high, almost exclusively due to infectious diseases. In the 1980s, the BHP founder, Prof. Peter Aaby, discovered that measles vaccine reduced child mortality much more than explained by prevention of measles infection. It appeared that measles vaccine had beneficial “non-specific effects” (NSEs), strengthening the immune system, and lowering the risk of dying from infections in general.

This led to an investigation of all the childhood vaccines. Unknown to most people, the childhood vaccines were never investigated for their effects on other infections, just the target infections(s). We discovered that all the vaccines we studied had NSEs.

A pattern emerged. All the live vaccines we studied had beneficial NSEs. However, for DTP vaccine, a non-live vaccine, we consistently found the vaccine to be associated with negative NSEs, particularly for girls. Hence, despite being protected against three deadly diseases, girls who received DTP vaccine had higher risk of dying than girls, who did not receive DTP vaccine, and DTP-vaccinated girls had higher risk of dying than DTP-vaccinated boys, even though the opposite was the case after live vaccines.  

We went to WHO with this worrying safety signal. In the first place, WHO commissioned some other sites to test our findings. These studies came out with extremely positive effects of DTP vaccine. However, they had used a flawed methodology, something that was acknowledged in 2006, and led WHO to declare that they would "keep a watch on the evidence of non-specific effects of vaccination".

Studies showing non-specific effects of vaccines continued to accumulate and in 2013, WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) established a working group on the non-specific effects of vaccines and conducted a review of the NSEs of the live measles and BCG vaccines and the non-live DTP vaccine. The review was published in BMJ in 2016. A total of 10 DTP studies were included in the analysis. While the two live vaccines were observed to reduce overall mortality much more than explained by the prevention of the target diseases, it was opposite for DTP vaccine, for which the reviewers concluded that “Receipt of DTP (almost always with oral polio vaccine) was associated possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys”. Receiving measles vaccine or BCG vaccine with of after DTP vaccine was associated with lower mortality than having DTP as the most recent vaccine. The reviewers recommended that the evidence “does indicate a need for randomised trials to examine the positioning of DTP in the vaccine schedule”.

At their meeting in April 2014, WHO’s SAGE tasked the committee IVIR-AC with defining the research questions to be studied in relation to NSEs. However, no studies in relation to DTP have apparently been planned, now almost 10 years after the meeting.

After the WHO review, we went back to the old records. BHP had introduced DTP vaccine in the community in the 1980s, believing it to be beneficial. However, when we got the data entered and analysed, we found further confirmation of negative NSEs of DTP vaccine. The best data was in the 3-5-month-old children, because in this age group, since DTP vaccine was given at 3-monthly weighing sessions, it was completely random (dependent on the birth date) if a child was vaccinated or not.

In this “natural experiment” covering data from 1981-83, children, who received DTP vaccine had 5 times higher mortality than children who had not yet received DTP vaccine. This was more pronounced for females (10 times higher) than for males, but the result did not reach significance. This is presumably the study that Robert F Kennedy Jr is referring to.

In subsequent studies of older children in the same period, we found similar results, and in 2018 we published a combined analysis of the three studies conducted during the introduction.

The analysis showed that the introduction of DTP vaccine in Guinea-Bissau was associated with a 2-fold increase in overall mortality. In girls, the estimate was a 2.60 (95% CI=1.57–4.32)-fold increase in mortality. Noteworthy, these studies were published after the WHO review. Had they been included in the WHO review, the negative effect of DTP vaccine would have been stronger.

In 2020, we reviewed all the data, in connection with a major review of the non-specific effects. Including all the studies with prospective follow-up, also the new studies, for a total of 17 studies, being DTP vaccinated vs. not being DTP vaccinated was associated with 2.07 (95% CI=1.60-2.67)-fold higher mortality. The estimate was 2.54 (1.68-3.86) in females. Among DTP-vaccinated children, females had almost 50% higher mortality than males (1.47 (1.18-1.84)). A dose-response has been observed, with the female-male mortality ratio increasing with each additional dose of DTP vaccine.

DTP is not the only vaccine that is associated with increased overall female mortality. The same pattern has been seen for now six non-live vaccines (See the table below). Importantly, the opposite pattern is seen for live vaccines. They are associated with beneficial NSEs and decreased overall mortality, particularly for females. No bias can explain why only non-live vaccines should be negative for females.

Importantly, since the data shows that the negative effect is abrogate when a live vaccine is given, it should be possible to design vaccination programs that include the important non-live vaccines that protect against deadly diseases, but just make sure that children spend as much time as possible with a ”live-vaccine-last”.

In conclusion, Robert F Kennedy Jr is not correct that we were sent out by the Danish government to study the effect of DTP vaccine. Bill Gates was not involved. We are independent researchers, who were driven by a first discovery that measles vaccine had very beneficial NSEs.

One of our DTP studies was a recent analysis of the "natural experiment" that took place when DTP vaccine was introduced in Guinea-Bissau 30 years ago. It showed that receiving DTP vaccine vs. not yet receiving DTP vaccine was associated with 5-fold significantly higher mortality. It was 10-fold higher for females, but it was not independently significant for girls.

However, this is just one of many studies of DTP vaccine that all point in this direction. Most of them are from Guinea-Bissau, but the findings have been the same in e.g., Benin, India and Malawi.

The conclusion is very clear: The whole-cell DTP vaccine used in low-income countries is associated with increased mortality for females. The observation has not been contradicted by good prospective studies. What remains unclear is why WHO does not act. Therefore, we welcome that Robert F Kennedy Jr shares the story about DTP vaccine, even though he got some details wrong.

Below follows a list of some of the studies showing negative non-specific effects of DTP vaccine in females. No good study of DTP given without BCG and with prospective follow-up has contradicted the findings.

Interested in knowing more?

TEDx about NSEs

A good layman article telling the story about NSEs

References:

Kristensen I, et al. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435–8.

Aaby P, et al. Routine vaccinations and child survival in war situation with high mortality: effect of gender. Vaccine 2002;21:15–20.

Aaby P, et al. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: re-analysis of West African studies. Lancet 2003;361:2183–8.

Aaby P, et al. The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study. Int J Epidemiol 2004; 33: 374–80.

Aaby P, et al. Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs. Int J Epidemiol 2004; 33:367–73.

Veirum JE, et al. Routine vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine 2005; 23: 1197-204

Aaby P, et al. Sex differential effects of routine immunizations and childhood survival in rural Malawi. Pediatr Inf Dis J 2006;25:721–7.

Aaby P, et al. Age-specific changes in the female-male mortality ratio related to the pattern of vaccinations: an observational study from rural Gambia. Vaccine 2006; 24:4701–

Aaby P, et al. Increased female-male mortality ratio associated with inactivated polio and diphtheria-tetanus-pertussis vaccines: Observations from vaccination trials in Guinea-Bissau. Pediatric Infectious Disease Journal 2007; 26: 247-52.

Aaby P, et al. DTP with or after measles vaccination is associated with increased in-hospital mortality in Guinea-Bissau. Vaccine 2007; 25: 1265-9                                   

Benn CS, et al. Why worry: vitamin A with DTP vaccine? Vaccine 2007; 25:777–9.

Benn CS, et al. Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana vitamin A supplementation trial. Am J Clin Nutr 2009; 90:629–39.

Aaby P, et al. Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial. Arch Dis Child 2012:97:685–91

Benn CS, et al. Diphtheria-tetanus-pertussis vaccination administered after measles vaccine: Increased female mortality? Pediatric Infectious Disease Journal 2012; 31: 1095-7.

Aaby P, et al. Testing the hypothesis that diphtheria-tetanus-pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open 2012; 2:e000707.

Hirve S, et al.. Non-specific and sex-differential effects of vaccinations on child survival in rural western India. Vaccine 2012;30:7300–8.

Krishnan A, et al.. Non-specific sex-differential effect of DTP vaccination may partially explain the excess girl child mortality in Ballabgarh, India. Trop Med Int Health 2013;18:1329–37

Aaby P, et al. Sex-differential and non-targeted effects of routine vaccinations in a rural area with low vaccination coverage: Observational study from Senegal. Trans Roy Soc Trop Med Hyg 2015;109:77–85.

Higgins JPT, et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 2016;355:i5170.

Aaby P, et al. The WHO review of the possible nonspecific effects of diphtheria-tetanus-pertussis vaccine. Pediatr Infect Dis J 2016; 35: 1247–57.

Aaby P, et al. Is diphtheria-tetanus- pertussis (DTP) associated with increased female mortality? A meta-analysis testing the hypotheses of sex-differential non-specific effects of DTP vaccine. Trans R Soc Trop Med Hyg 2016; 110: 570–81

Aaby P, Ravn H, Benn CS, et al. Child mortality after inactivated vaccines versus standard measles vaccine at nine months of age: a combined analysis of five cross-over randomised trials. Pediatr Infect Dis J 2016; 35:1232–41.

Andersen A, et al. Sex-differential effects of diphtheria-tetanus-pertussis vaccine for the outcome of paediatric admissions? A hospital based observational study from Guinea-Bissau. Vaccine 2017; 35:7018–25

Welaga P, et al. Fewer out-of-sequence vaccinations and reduction of child mortality in Northern Ghana. Vaccine 2017; 35:2496–503.  

Mogensen SW, et al The introduction of diphtheria-tetanus-pertussis and oral polio vaccine among young infants in an urban African community: a natural experiment. EBioMedicine 2017; 17: 192–98.

Aaby P, et al. Evidence of increase in mortality after the introduction of diphtheria-tetanus-pertussis vaccine to children aged 6–35 months in Guinea-Bissau: a time for reflection? Front Public Health 2018; 6: 79.

Hanifi SMA, et al. Diphtheria-tetanus-pertussis (DTP) vaccine is associated with increased female-male mortality rate ratios. A meta-analysis of studies of DTP administered before and after measles vaccine. J Infect Dis. 2020 Oct 30.      

Clipet-Jensen C, et al. Out-of-Sequence Vaccinations With Measles Vaccine and Diphtheria-Tetanus-Pertussis Vaccine: A Reanalysis of Demographic Surveillance Data From Rural Bangladesh. Clin Infect Dis. 2021 Apr 26;72(8):1429-1436

Øland CB, et al. Reduced Mortality After Oral Polio Vaccination and Increased Mortality After Diphtheria-tetanus-pertussis Vaccination in Children in a Low-income Setting. Clin Ther. 2021 Jan;43(1):172-184.e7