Considering recent studies in humans, looking at a single dose of the Johnson & Johnson vaccine followed by an mRNA booster, as well as plentiful studies in animal models that addressed heterologous prime/boost regimens with adenovirus-vectored vaccines and mRNA vaccines in the context of COVID-19 as well as other diseases, the data suggest that this type of regimen is extremely immunogenic and would very likely improve protective efficacy compared to a single dose of the Johnson & Johnson vaccine. One endpoint that was not addressed in the human studies that we and others have seen in animal models is that this heterologous prime/boost regimen (adenovirus followed by mRNA) significantly enhances T cell responses to levels that cannot be achieved by each vaccine alone. These T cell responses could play an important role in protection against variants of concern. Of course, this needs to be evaluated in humans, but given the consistency between animal model and human studies that evaluated antibody responses following this heterologous vaccination regimen, it’s very likely that enhancement of T cell responses would be observed in humans. In the event that heterologous boosters are not offered and a homologous booster for Johnson & Johnson vaccinated individuals is made available, the data suggest that this would likely provide a benefit, although a heterologous booster with mRNA would be ideal for reasons described above.

Three studies to date have already shown us that administering “mixed vaccines” (one mRNA vaccine and one DNA/adenovirus vector vaccine in either order)  increases the immune response over two shots of the same vaccine (one study in the UK, one in Spain and one in Germany).  The National Institutes of Health mix and match study shows us the same thing, at least in terms of an antibody response. The Johnson & Johnson vaccine followed 12 or more weeks later by an mRNA vaccine (either Moderna or Pfizer) leads to a higher antibody response (by more than ten-fold) than giving a Johnson & Johnson booster.  However, the second dose of a Johnson & Johnson vaccine, as reported by the company, does provide high vaccine effectiveness (94%) and a strong T cell and antibody response.  Given this mix-and-match study evidence, the Food and Drug Administration is likely to eventually approve an mRNA dose following an initial Johnson & Johnson vaccine dose.  At that point, those who got an initial Johnson & Johnson vaccination can either receive a second dose of Johnson & Johnson two months later or a second dose with an mRNA vaccine, either Moderna or Pfizer.  The FDA is likely to make the recommendation on this mRNA shot after a Johnson & Johnson vaccination at a later meeting, as the FDA meeting today did not yet make that determination.

Recent National Institutes of Health data shows that so-called ‘heterologous’ boosters elicit stronger immunity than a second Johnson & Johnson dose. There are caveats to this study, perhaps the most important being that it has a relatively small number of participants. This could mask safety risks that will only be apparent once many more people receive mRNA boosters. With that said, there is also a very real risk that suboptimal boosting could increase vulnerability to SARS-CoV-2 infection into the winter and beyond. Weighing these risks and benefits is inherently subjective, and reasonable scientists might disagree about the optimal balance. To me, a higher antibody titer that confers better protection from COVID would be worth accepting that there would be some unknowns that cannot become clear until later. If I were given the choice, I would prefer an mRNA booster. If that is not an option, a second Johnson & Johnson booster would be better than no booster at all.