4th dose of mRNA Covid-19 vaccine significantly increases protection in age 60+

In a recent study published in the New England Journal of Medicine, researchers compare the efficacy of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Pfizer-BioNTech BNT162b2 third- and fourth-dose vaccinations in Israel.

Study: Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. Image Credit: WESTOCK PRODUCTIONS / Shutterstock.com

Background

On January 3, 2022, the Israeli Ministry of Health began national SARS-CoV-2 fourth-dose vaccination services for at-risk populations including people over the age of 60 and immunocompromised individuals around four months following receipt of their third vaccine dose. Other nations that have initiated the coronavirus disease 2019 (COVID-19) fourth-dose vaccination campaigns included the United States and the United Kingdom. 

The SARS-CoV-2 fourth-dose vaccine rollout was initiated in response to persistent waves of COVID-19 cases caused by the SARS-CoV-2 Omicron (B.1.1.529) variant, combined with waning protection after the third boosting dose of the COVID-19 vaccines. The effects of the Omicron-driven wave were even observed in nations with successful COVID-19 mass-vaccination initiatives.

A recent report offered real-time proof of the efficacy of a fourth dose of the SARS-CoV-2 BNT162b2 vaccine and indicated that this additional booster is more efficient in preventing COVID-19 and severe SARS-CoV-2 infection than three doses alone. Nevertheless, the trial did not provide information on the efficacy of a fourth dose in preventing additional COVID-19 outcomes, such as hospitalization and mortality rates. Furthermore, several potentially relevant confounders, such as the presence of comorbidities, were not addressed.

About the study

In the present study, the scientists evaluated the early efficacy of a fourth dose of the SARS-CoV-2 BNT162b2 vaccine in preventing a range of COVID-19-associated outcomes in high-risk populations by analyzing data retrieved from the largest Israelian healthcare facility between January 3 and February 18, 2022, while controlling for possible confounders.

The authors assessed five SARS-CoV-2-related outcomes, of which included: polymerase chain reaction (PCR)-confirmed COVID-19, symptomatic SARS-CoV-2 infection, COVID-19-associated hospitalization, severe SARS-CoV-2 infection, and COVID-19-associated death.

Further, the confounding factors controlled in this research were age, gender, residency location, population sector, the calendar month of third-dose receipt, number of chronic preexisting comorbidities characterized as severe COVID-19 risk factors by the U.S. Centers for Disease Control and Prevention (CDC), and number of hospitalizations in the last three years.

The scientists examined the relative efficacy of a fourth dose of the COVID-19 vaccine as compared to a third dose administered nearly four months prior in individuals aged 60 years or above at the personal level. In addition, both cohorts were matched by various clinical and sociodemographic variables. A total of 182,122 matched pairs were included in the primary analysis.

Study findings

The comparative vaccine efficacy in one week to one month following the fourth BNT162b2 vaccine dose was approximated to be 45% against PCR-confirmed COVID-19, 55% against symptomatic SARS-CoV-2 infection, 68% against COVID-19-linked hospitalization, 62% against severe SARS-CoV-2 infection, and 74% against COVID-19-associated mortality. The corresponding estimates in two weeks to one-month post-fourth dose were 52%, 61%, 72%, 64%, and 76%, respectively.

In one week to a month following the fourth dose, the variation in the absolute risk between three and four doses was 180.1 cases/100,000 individuals for COVID-19-linked hospitalization and 68.8 cases/100,000 people for severe SARS-CoV-2 infection. Furthermore, estimates of relative vaccine efficacy against reported SARS-CoV-2 infection in sensitivity analyses were comparable to values in the primary evaluations.  

Individuals in the fourth-dose group have a low risk of confirmed COVID-19 during the initial days of follow-up shortly after their vaccination. Further, vaccinated people underwent SARS-CoV-2 testing less frequently in the initial few days following immunization, which was likely because they associated any symptoms with the vaccine’s adverse effects. Nevertheless, this bias was a temporary event, evidenced by almost equal risks in the three and four-dose vaccine groups on days five and six. 

Following this, the fourth dose of the vaccine began to act around week one, with efficacy progressively increasing to a steady level around week two. Given the notably modest variation between the two groups on days five and six, the majority of the ensuing difference might be attributed to the efficacy of a fourth vaccine dose.

Conclusions

The findings of the current real-world study demonstrated that a fourth dose of the COVID-19 BNT162b2 vaccine was effective against the SARS-CoV-2 Omicron variant, at least initially. The study showed that the BNT162b2 vaccine fourth-dose enhances protection against PCR-confirmed COVID-19, symptomatic SARS-CoV-2 infection, COVID-19-linked hospitalization, severe SARS-CoV-2 infection, and COVID-19-associated mortality when compared to a third booster dose given at least four months prior among individuals over the age of 60 years.

Extended follow-up will provide a more in-depth evaluation of the fourth dose’s long-term protection. Although these data help assuage certain concerns, the authors state that more research is needed to establish whether vaccinating less often or delivering a mix of multiple SARS-CoV-2 vaccines is a better long-term policy to curb the ongoing COVID-19 pandemic.  

Taken together, the present work depicted that a fourth BNT162b2 COVID-19 vaccine dose was beneficial in minimizing the short-term risk of SARS-CoV-2-associated outcomes in at-risk individuals who had previously received a third vaccine dose.