Second COVID Booster Has "Marginal Benefits" in Small Study

Aude Lecrubier

April 14, 2022

This article was originally published in French on Medscape.

Israel — Administering a second COVID-19 vaccine booster offers little benefit for healthy healthcare professionals, according to a study conducted at the Sheba Medical Center in the suburbs of Tel-Aviv. The investigators talk about "marginal benefits" while specifying that "older and vulnerable populations were not assessed."

In this open-label, nonrandomized clinical study, investigators evaluated the immunogenicity and safety of a fourth dose of the Pfizer-BioNTech or Moderna vaccine booster administered 4 months after the third dose of a three-dose series of the Pfizer-BioNTech vaccine.

Of the 1050 eligible healthcare professionals, 154 (average age 59 years) received the fourth Pfizer dose and, 1 week later, 120 (average age 55 years) also received the fourth Moderna dose. For each participant, two age-matched controls were selected from the remaining eligible participants.

After the fourth dose, both messenger RNA (mRNA) vaccines increased neutralizing antibody titers to titers slightly higher than those obtained after the third dose, with no significant difference between the two vaccines. At the same time, antibody levels in the control group continued to decrease.

Antibody Production, Limited Efficacy

Both vaccines induced an increase in neutralization of the Omicron variant and other viral strains that was similar to the response after the third dose.

The fourth dose did not lead to any significant adverse reactions in most recipients beyond mild local and systemic symptoms.

By performing weekly PCR tests, the investigators observed that 25% of participants in the control group were infected with the coronavirus vs 18.3% of participants in the group that received the Pfizer booster and 20.7% of participants in the group that received the Moderna booster.

The vaccine's efficacy against COVID infections was 30% for the Pfizer-BioNTech booster and 11% for the booster administered with the Moderna vaccine. The efficacy in preventing symptomatic disease was 43% with the Pfizer booster and 31% with the Moderna booster.

High Viral Loads

Most of the infected healthcare professionals reported negligible symptoms, both among the controls and among those who received the second booster. However, viral loads were relatively high, so individuals were very likely contagious in all cases.

Small Population

The main limitations of the study are its small population size and nonrandomized design. Furthermore, there was a 1-week gap between the injections in the two intervention groups (Moderna and Pfizer), which could have led to potential biases.

In addition, adherence to the weekly SARS-CoV-2 screening was slightly lower in the control group.

Finally, regarding positive cases, because genome sequencing was not performed, it is not certain that all the infections were caused by the Omicron variant; "however, during the study period, Omicron accounted for 100% of the isolates," said the investigators.

"Our data provide evidence that a fourth dose of mRNA vaccine is immunogenic, safe, and somewhat efficacious (primarily against symptomatic disease)," concluded the authors. They added that "our results suggest that maximal immunogenicity of mRNA vaccines is achieved after three doses and that antibody levels can be restored by a fourth dose. Furthermore, we observed low vaccine efficacy against infections in healthcare professionals, as well as relatively high viral loads, suggesting that infected individuals were contagious."

The authors' conflicts of interest are listed in the correspondence at


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