Study finds third dose of BNT162b2 or mRNA-1273 is moderately effective against post-vaccination COVID-19 infection

Clinical Trials & Research

The onset of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to intensive efforts to develop effective and safe vaccines against the virus and arrest its spread. The earliest to be developed were the BNT162b2 and mRNA-1273 vaccines, from Pfizer/BioNTech and Moderna, respectively, both based on nucleic acid platforms.

Study: Effectiveness of a third dose of BNT162b2 or mRNA-1273 vaccine for preventing post-vaccination COVID-19 infection: an observational study. Image Credit: davide bonaldo/Shutterstock

These were reported to protect vaccine recipients against 94-95% of symptomatic and severe COVID-19. Real-time follow-up shows that their effectiveness wanes over time, allowing reinfection or breakthrough infection to occur even in the fully vaccinated. In fact, in countries with a high vaccination rate, the latter account for most current infections.

This has worsened with the rise of the Delta variant, which prompted a round of booster doses six or more months from the primary regimen. A recent preprint examines the effectiveness of this strategy, using data from the Veterans Health Administration (VHA) to compare the protection it offered against infection with that of the primary two-dose regimen.

By the latter half of November 2021, the US Centers for Disease Control and Prevention (CDC) reported that an estimated 41% of vaccinated people above 65 years had received a third dose of the vaccine. Yet, data on its clinical effectiveness is still lacking.

Many studies have, of course, described rapid and significant rises in antibody titers following the booster dose. Still, the correlation with protection against clinical disease is not clear as of now, except observational studies in Israel that show a reduced risk of disease following the third booster dose compared to the primary vaccine regimen.

The current study, which appears on the medRxiv* preprint server, used VHA electronic health records (EHR) to estimate the effectiveness of the booster dose in the USA against post-vaccination COVID-19. The treatment and control cohorts were matched for age, sex, and other demographic parameters, for positive tests for the virus (by polymerase chain reaction, PCR) and underlying medical conditions, as well as the date of completion of the primary vaccination series.

What did the study show?

The study included almost 440,000 fully vaccinated individuals, with almost equal shares of the Pfizer and Moderna vaccines. About 36% and 27% then received a third dose of either vaccine, respectively. There were ~74,000 and 55,000 matched pairs of primary series vs. booster dose recipients for the Pfizer and Moderna vaccines, respectively.

The median age was 72 in both sets, with ~94% being male in both groups. Less than 2% in either group had ever tested positive for the virus, but most were not tested in the 90 days before the study began.

Over a follow-up of 16 days (median), in the BNT162b2 group, the incidence of SARS-CoV-2 infection was 0.8% and 0.4% of primary series and third dose recipients, respectively, while hospitalizations occurred in 0.2% and 0.1% of the two groups, respectively. In the other group, the numbers were 0.6% and 0.3% for infection, and 0.2% vs. 0.1% of either subset underwent hospitalization, respectively.

This means that the BNT162b2 and mRNA-1273 third-dose boosters prevented almost half the post-vaccination infections and hospitalizations, respectively, in this elderly cohort, irrespective of age. However, there was a slightly higher degree of protection in healthier individuals.

Overall, hospitalization risk was not significantly affected by the third-dose booster in the current analysis of older patients.

When the follow-up was extended to 90 days, the incidence of infection and hospitalization in the BNT162b2 primary series cohort was ~2% and 0.5%, respectively. However, following third-dose booster shots, the incidence of infection was lower by almost 50%.

Over the same period, the mRNA-1273 primary series vs. third-dose booster cohorts showed 2.6% infection incidence and 0.5% hospitalization rates, which dropped by approximately 50% following the third dose. This difference was observable first within five days of the third dose, for infection, and ten days, for hospitalization.

What are the implications?

This study leveraged data from the largest healthcare system in the United States to compare the real-time effectiveness of a third dose of the vaccines compared to the primary series. There was a 45% reduction in infection and hospitalization risk with the third dose of the BNT162b2 vaccine and a comparable 47% and 50% reduction with the Moderna mRNA-1273 third-dose booster.

Our findings demonstrate moderate reductions in post-vaccination infections in persons who receive a third dose of vaccine 6 months after completing the primary series of BNT162b2 or mRNA-1273; improvements in documented SARS-CoV-2 infection and COVID-19 hospitalization occur within 5 and 10 days of administration of a third dose, respectively.”

Interestingly, the findings in this study do not mirror the high effectiveness seen with the Pfizer third-dose booster seen in Israel, perhaps because the incidence of COVID-19 in the two countries was quite dissimilar during the study periods. In addition, adherence to non-pharmaceutical interventions (NPIs) designed to prevent COVID-19 transmission was quite different in the two countries, which would bias the Israeli study towards higher effectiveness rates.

Thirdly, the Israeli study involved younger, healthier individuals. The current study is more generalizable in that it represents people with a higher risk of infection at baseline. It shows a moderate reduction in the risk of mild and severe infections post-vaccination with the third dose of either vaccine, probably due to the hike in neutralizing antibody levels.

An earlier study, also from Israel, showed that the viral load in a fully vaccinated individual is lower than in an unvaccinated person, for about six months, with the BNT162b222 vaccine. This waning is corrected by the third dose, but the duration of this effect remains, obviously, unclear.

It is possible that people who seek out third-dose boosters at this early time point may also be those more concerned about their risk of infection, and therefore more likely to adopt protective measures like mask use and social distancing, especially with other underlying illnesses. This could contribute to the observed risk reduction by reducing the exposure to infection.

The effectiveness in also preventing secondary infections among the contacts of the vaccinated individuals is unknown. One UK study has shown that despite similar viral loads in vaccinated vs. unvaccinated individuals following infection, the virus is cleared faster in the former. However, the rate of secondary transmission of the infection to household contacts shows no difference between vaccinated and unvaccinated individuals.

The Delta variant is also found to spread with equal ease from fully vaccinated individuals to their contacts. Further suppression of spread may occur with greater vaccination coverage, reducing the susceptible pool in the population.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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