Research published in The New England Journal of Medicine offers the first insights into the efficacy of a fourth COVID-19 vaccine dose. The data from a health care worker trial in Israel found a fourth dose only offers “marginal benefits” over three doses, however, experts claim the extra booster shot is likely to be more protective in elderly and vulnerable populations.
Late last year Israel became the first country in the world to begin rolling out a fourth COVID-19 vaccine dose. Initially focusing on immunocompromised populations, the fourth dose program is currently still limited to those over the age of 60, health care workers and others who may be at high risk of infection due to their work.
Recent research from the U.S. Centers for Disease Control and Prevention (CDC) has confirmed a third COVID-19 vaccine dose is crucial in protecting against severe disease from the Omicron variant. However, the data also revealed third-dose vaccine protection from infection significantly drops off after around four months.
So does a fourth dose restore that protection, and will the extra booster be necessary for most people in the near future?
The new peer-reviewed and published data reports on a trial testing a fourth dose of either Moderna or Pfizer’s mRNA COVID-19 vaccine in health care workers more than four months past their third dose. The study found the fourth dose was safe and restored antibody levels up to what was seen after three doses. But in terms of real-world infection prevention, the study found only small differences in positive Omicron cases when comparing the four-dose groups with a three-dose control.
“Overall, 25.0 percent of the participants in the control group were infected with the Omicron variant, as compared with 18.3 percent of the participants in the BNT162b2 [Pfizer] group and 20.7 percent of those in the mRNA-1273 [Moderna] group,” the researchers wrote. “Vaccine efficacy against any SARS-CoV-2 infection was 30 percent.”
The researchers note this cohort was too small to clearly determine the accurate efficacy of a fourth dose. It is also stressed that this cohort was filled with young and healthy subjects so there is no insight into the value of a fourth dose in more vulnerable populations.
“… we observed low vaccine efficacy against infections in health care workers, as well as relatively high viral loads suggesting that those who were infected were infectious,” the researchers concluded. “Thus, a fourth vaccination of healthy young health care workers may have only marginal benefits.”
Another study out of Israel, yet to be peer-reviewed and published, has tracked the efficacy of fourth doses in those over the age of 60. It found a fourth dose in older populations significantly reduces symptomatic infections and severe disease compared to three doses.
"The results of this study suggest that a fourth dose could increase protection against severe illness relative to three doses that have been administered over four months ago," the researchers wrote in the pre-print study. "Giving the fourth dose to individuals who were at risk to develop severe disease has been instrumental in limiting the burden on hospitals in Israel during the fast and wide-spreading Omicron surge."
Julian Tang, a clinical virologist from the University of Leicester, said this new study is useful. He agrees the benefits may be marginal for a broad fourth-dose program right now in all adults but argues another booster dose is probably beneficial in older and vulnerable populations.
“Ideally, we need new COVID-19 vaccines designed specifically against Omicron if we want to improve this protection for the most vulnerable – in the same way that we update the seasonal flu vaccine each year – to ensure the best possible match against the currently circulating virus strain,” said Tang.
Simon Clarke, from the University of Reading, said we may have squeezed the most we can out of these current vaccines. Putting aside the potential need for a fourth vaccine dose in vulnerable populations, Clarke said we need to update our vaccines to better target the new variants circulating.
“These two vaccines generate the best response against variants that are no longer in circulation,” said Clarke. “It’s about time that vaccines caught up with the variants that are currently infecting people, otherwise giving fourth doses might be like old Generals fighting old wars.”
Nevertheless, not everyone is interpreting this new study as a reason to pause broad fourth-dose vaccine programs. Raina MacIntyre, an expert on the prevention and control of infectious diseases, explained how even if a fourth dose only offers modest extra protection from infection it can still be significantly valuable when disease burden is high.
“The 11-30 percent VE [vaccine effectiveness] against any infection will make a substantial impact on transmission at a population level,” MacIntyre explained on Twitter. “The impact of vaccines is a function of VE, coverage and incidence of infection. When incidence is high, even a vaccine of modest VE can have a major population impact.”
Here is a slide which demonstrates the population impact of a vaccine of modest efficacy when disease burden is high - note the high VE in kids vs low VE in adults, but much greater burden of infection = more impact of a lower VE vaccine in older people pic.twitter.com/QJ6xJxLrs0
— Global Biosecurity (@Globalbiosec) March 17, 2022
MacIntyre also pointed out health care workers are likely to be exposed to much higher levels of the virus than those in the general community. And because we know there is a dose-response relationship to viral exposure it is possible a fourth dose will be more effective in members of the general population. Alongside good masking and robust ventilation protocols MacIntyre argues a fourth dose of the current vaccine will likely offer most people a “fighting chance of avoiding COVID-19.”
Most experts are in agreement that the conversation around a fourth COVID-19 vaccine dose is one of “when” that strategy should be deployed rather than “if” it will be necessary in the first place. Albert Bourla, CEO of Pfizer, has recently argued a fourth dose is necessary “right now.” A submission has already been made by Pfizer to the Food and Drug Administration (FDA) for a broad fourth-dose approval in the United States.
Marco Cavaleri, head of vaccine strategy at the European Medicines Agency, recently expressed reticence at triggering fourth-dose programs at this point in time. He said, although there are currently significant spikes of COVID-19 cases in many European countries, it is unclear whether the resurgence is due to waning vaccine immunity or the broad lifting of many social restrictions.
"I want to reiterate there is not yet enough evidence ... supporting a recommendation for a second booster shot in the general population," Cavaleri said.
The new study was published in The New England Journal of Medicine.
