The emergence of the SARS-CoV-2 Delta and Omicron virus variants has raised the importance of booster vaccines. The broader immunity from a third dose of COVID vaccine appears to provide better protection against both the original virus strain and new variants. In addition, a few of the vaccines available throughout the world, particularly the single dose Johnson and Johnson vaccine, provide protection that essentially goes away in six months making a booster dosage crucial.
Most government agencies, including The United States CDC, have recommended getting a booster with any COVID-19 vaccine regardless of what your initial dose involved. But there has been no direct comparison about the efficacy and safety of different booster regiments.
This week, a new study in the journal Lancet did a direct comparison of seven different third dose booster vaccines in combination with primary vaccinations. The study was performed in the UK, so it involved primary immunization with the Pfizer/NBioTech and the AstraZeneca chimpanzee virus vaccine, since those were the two vaccines first approved in that country.
The researchers compared seven different vaccines as boosters. All were given at the recommended booser dose, which is often different from the initial dose (Moderna, for example, is ½ the amount given in initial two doses).
In addition to AstraZeneca and Pfizer, they used two other brands approved in the U.S. — Johnson & Johnson and Moderna. They also examined Novavax, which is approved in parts of Europe, and two vaccines not authorized anywhere: an mRNA vaccine from CureVac (which failed clinical trial as a primary vaccine) and a vaccine from Valneva made from inactivated coronaviruses. As a control group some of the volunteers were given a meningitis vaccine instead of a COVID-19 vaccine.
The study was well controlled, and all groups appeared equal in the numbers and types of individuals immunized. The investigators looked at antibody and cellular immune responses, as well as adverse reactions (headaches, fevers, pain, etc.) and compared all the outcomes using appropriate statistics.
While the authors and UK investigators hailed the results as indicating “all the boosters worked,” the efficacy differences between the regimens were highly significant. The improvements in antibody responses ranged from 30 to 1,000-fold!
The clear winners were the mRNA vaccines that gave the strongest antibody improvements and cellular immune responses as boosters. These vaccines also gave the best overall immunity of all the combinations when the Pfizer vaccine was given as the initial two doses. The combinations that were least effective involved the unapproved vaccines from Valneva and CureVac. Novavax was much better than those vaccines, but not as good as the Moderna and Pfizer.
Overall the side effects from booster vaccines were minimal and did not involve any serious reactions, but differences were present. The adenovirus-based vaccines from AstraZeneca and Johnson and Johnson showed only moderate efficacy to boost immunity (not as effective as either Pfizer or Moderna), but had worse side effects, especially when boosting the Pfizer/BNT primary vaccine. Only the most immunogenic and reactive mRNA vaccine, Moderna, approached this level of side effects.
Control=quadrivalent meningococcal conjugate vaccine. ChAd=ChAdOx1 nCoV-19 vaccine, Oxford–AstraZeneca. NVX=NVX-CoV2373 vaccine, Novavax. NVX half=half dose of NVX-CoV2373 vaccine. BNT=BNT162b2 vaccine, Pfizer–BioNTech. VLA=VLA2001 vaccine, Valneva. VLA half=half dose of VLA2001 vaccine. Ad26=Ad26.COV2.S vaccine, Janssen. m1273=mRNA1273 vaccine, Moderna. CVn=CVnCoV vaccine, Curevac.
While the intensity of immunity needed to protect against COVID-19 is not exactly defined, in general most immunologists feel (and there is data to support this) that a higher the level of immunity results in better protection. So, it is likely that the improved booster immunity seen with the best combinations tested could lead to significantly better defense against COVID infection.
Bottom line: get Pfizer or Moderna as your booster shot no matter what vaccine you originally received.
Pandemic Pondering 
Hi Dr. Baker,
Did these studies evaluate the effectiveness of the booster in preventing clinical illness to the Omicron variant? My understanding is that out of about 50 mutations in the Omicron variant, a little over 30 of them are in the spike protein alone. Given that the boosters are using the formulation for the original SARS-CoV-2 virus spike protein, I would think that the boosters would be at least somewhat less effective in providing actual immunity (vs. increased antibody blood concentrations, presumably antibodies to the original spike protein vs. omicron). In other words, do increased antibody concentrations to the old spike protein make much of a difference, if any, to infection via the new spike protein? Do you know of any research being done in this area, which seems to me to be the critical outcome variable here?
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I think the difference with the booster is a spreading of antibody binding sites to include areas not mutated in omicron. Withe repeated exposure “epitope spreading” increases the number of sites recognized by the immune system. This probably evolved to deal with virus variants that try to escape immunity. And remember, cellular epitopes are less likely to be altered than antibody because they involve much smaller parts of the proteins. This provides a second level of protection.
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I had Covid in Oct 2020 and then got two doses of Moderna in Feb/Mar so I believe I’ve gotten two boosters already (and had the side effects for 36-48hr both times to proof it). Does a third booster really add anything? I’m more inclined to favor exposure to omicron as a ‘third booster’….though of course I’m on intentionally seeking that option. What is wrong with my logic? (And, why can’t all these studies look at those who have had Covid vs. those who haven’t? There are certainly no lack of subjects.)
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Unfortunately no one has systematically examined this. I think your logic is correct, though, and doubt that you would get very ill if you encountered another variant; either delta or omicron.
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