Fourth COVID vaccination shot may not be necessary for most people because it does not add significant protection


A team of researchers working at Israel’s Sheba Medical Center has found evidence that suggests a fourth COVID vaccination or second booster shot may not be necessary for most people because it does not add significant protection.

In their paper posted on the medRxiv preprint server, the team describes comparing people who were given a second booster shot with people who were not.

As the pandemic has progressed, medical researchers have worked hard to develop vaccines to keep people from getting sick and therapies to help those afflicted. As a result, vaccines were developed by several companies that proved to prevent serious infections.

Booster shots of the same vaccines were then found to provide protection again months later as immune response to the vaccines waned. Since that time, many people have wondered if they will need another booster shot as protection from the first booster starts to wane. In this new effort, the researchers sought to find the answer.

It was not a coincidence that the researchers were working in Israel – it is one of the few countries that has not waited to find out if a fourth shot is needed. Officials there have begun making second boosters available to those who want them.

To determine the efficacy of second booster shots, the researchers recruited 1,000 healthcare workers who were fully vaccinated and who had received a booster shot.

Two-hundred seventy-four received a second booster; the rest served as a control group. The researchers then measured antibody levels for all of the subjects.

They found that while the second booster did increase protection slightly, it was not by enough to justify its use – at least at this time. They also found that the second booster did not activate T cells.

They suggest their results should not frighten people, however; they believe that most people are still adequately protected from their first three shots. Still, they do suggest that older people and those at risk for other reasons get a second booster if they can.

Though such people were not included in the study, the researchers assume that any increase in protection for people more at risk is reason to get the shot.


This open-label, clinical trial was designed to assess the immunogenicity and safety of a fourth dose of two mRNA vaccines, BNT162b2 or mRNA1273, administered four months after the third dose in a series of three BNT162b2 doses (given on days 1, 21 and a booster dose 5-6 months later).

As secondary outcomes, we also assessed the cumulative incidence of all infections as well as symptomatic disease and calculated vaccine efficacy of the fourth dose (of either vaccine) compared to three doses of BNT162b2.

The major strengths of this study include the availability of the serologic history of the participants since initial vaccination, very intensive and meticulous follow-up, which included active weekly SARS-CoV-2 PCR testing, detailed information on comorbidities, vaccine history, serology history, symptoms and adverse events.

Our study found that the fourth dose did not lead to significant adverse events despite triggering mild systemic and local symptoms in the majority of vaccine recipients. Since the fourth dose was approved in Israel for individuals over 60 years old, HCW and immunocompromised populations above 18 years, future studies will investigate the safety of the fourth dose in larger cohorts.

Nevertheless, in light of numerous studies investigating the safety and reactogenicity of one, two and three mRNA vaccine doses7,11,15–17, our results suggest that the safety profile of the fourth dose is likely similar to that of previous doses.

Interestingly, greater reactogenicity in younger adults compared to those aged 60 or more, which was previously reported, was mostly observed in the BNT162b2 recipients and less so in the mRNA1273 recipients. Yet, our study was not powered to identify less than 20% difference in AE rates.

Our study was designed primarily to determine the immunogenicity of a fourth dose and to assess whether an mRNA heterologous fourth boost (i.e., mRNA1273 following three BNT162b2 prior doses) would be more immunogenic. Our results clearly show that both mRNA vaccines significantly induce IgG and neutralizing antibodies. Moreover, both vaccines induced ∼10 folds the specific neutralizing response against Omicron and other VOC.

As antibodies are found to be correlates of protection18–20 our serology results including the specific neutralizing ability against Omicron and the comparison to the third dose can also project on vaccine protection. Comparing the initial response to the fourth dose with the peak response following a third dose, did not demonstrate substantial differences in humoral response or in the amount of Omicron specific neutralizing antibodies (this study and Nemet et al.15).

Overall, these data raise the possibility that the fourth dose does not boost immunity but simply restores it to peak levels. It is yet to be observed whether the waning of this fourth dose will be at a similar rate as that observed after the third dose and whether it will differ between the two mRNA vaccine groups.

While our study was not originally designed to assess vaccine efficacy, which was only a secondary outcome, the rapid spread of Omicron and the meticulous study design, with rigorous active surveillance of all infections, allowed us to determine cumulative incidence following a fourth dose and assess vaccine efficacy despite the relatively small cohorts used.

Overall, during the study period 25% of the control groups were infected by SARS-CoV-2 and 18-20% of the vaccinated groups had concurrent breakthrough infections, leading to a low vaccine efficacy against infections of 11-30%, with relatively wide confidence intervals.

Moreover, most of the infected HCW, in all groups complained of only negligible symptoms, which in many cases would not have been tested or reported, without the active surveillance.

Yet, most of these infected HCW were potentially infectious, with relatively high viral loads. Thus, the major objective for vaccinating HCW was not achieved. The increased efficacy against symptomatic compared to asymptomatic infections found in this study suggest that the fourth dose may be more efficacious against severe disease and death, as was recently observed22. Therefore, older and vulnerable populations who are at higher risk for severe disease may benefit most from a fourth vaccine dose.

. . .

More information: Gili Regev-Yochay et al, 4th Dose COVID mRNA Vaccines’ Immunogenicity & Efficacy Against Omicron VOC (2022). DOI: 10.1101/2022.02.15.22270948


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