Two newly published studies indicate a fourth COVID-19 vaccine dose can substantially boost a person’s immunity and reduce the risk of infection compared to triple-dosed individuals. Most fourth-dose programs around the world are currently limited to the very old and vulnerable, however, experts are divided on whether more age groups should be offered an extra booster at this point in time.
Ever since the initial two-dose COVID-19 vaccine protocol started rolling out in late 2020 the ongoing question has been: when is another dose necessary? As 2021 progressed and new SARS-CoV-2 variants emerged it became clear that three vaccine doses were optimal for general protection against severe disease. But now in 2022 many are wondering when a fourth dose will be needed.
A new study published in The Lancet Infectious Diseases offers one of the most robust insights into immune responses to a fourth COVID-19 vaccine dose. The UK study closely measured a variety of immune biomarkers in elderly subjects who received their fourth vaccine dose approximately seven months after their third shot.
The results showed a fourth dose significantly boosted both antibody and T-cell responses to levels similar to those seen after three doses. In some cases those immune biomarkers were stronger after a fourth dose than after the third.
Interestingly, the study reported the efficacy of a fourth dose was associated with how much a third dose had waned in any given individual. Those subjects with persistent humoral and cellular immune responses from the third dose did not display strong benefits from a fourth dose.
“This finding was replicated in participants with a history of SARS-CoV-2 infection, indicating that there might be a ceiling or maximum anti-spike protein IgG titre and T-cell response and that the fourth dose might not boost humoral and cellular responses if the baseline response is high,” the researchers write in the study. “These individual data are important for policy makers as the benefit of a fourth dose might be less in people who already have high levels of immune responses from recent infection or vaccination.”
Another recently published study complements these results, comparing third and fourth vaccine dose COVID infection rates in a large number of elderly subjects. The research looked at around 1.2 million people over the age of 60 in Israel. Half of the cohort had received three COVID vaccine doses and the other half received four.
The study found a fourth dose lowered rates of infection by a factor of two compared to three doses. This protection from infection peaked at four weeks after the fourth dose. By the eight-week mark the study saw no difference in infection rates when comparing three- and four-dose cohorts.
However, protection from severe disease was significantly increased by a factor of three in the four-dose cohort. And this protection seemed to hold for at least six weeks, suggesting a fourth dose could be important in elderly and vulnerable populations.
Many parts of the world have already commenced fourth-dose vaccine programs but there is no consensus on who should be getting the extra boosters. The UK, for example, offers fourth doses to people over the age of 75, while the US set its bar at 50 years of age. Most countries are offering fourth doses to people with severe immunosuppressive illness, but not other vulnerable groups such as those with chronic diseases or cancer.
The big dilemma facing regulatory bodies around the world is how broadly should fourth doses be distributed right now. Some researchers, such as immunologist Danny Altmann from Imperial College London, argue these new findings affirm the value of widely pushing fourth doses across all age groups.
“Just because our first-generation vaccines wane rapidly and offer rather permeable protection nowadays, does not suggest we should give up and have no further boosters,” Altmann said to The Guardian. “On the contrary, [given] many of us, even with high apparent antibody levels, actually show [very little] protective neutralization of Omicron, there is all the more urgency to use [fourth] doses – in all age groups – to boost levels back up into the protective range.”
On the other hand, Adam Finn, a pediatrics researcher from the University of Bristol, argues there is no current need for healthy, young or middle-aged people to get a fourth vaccine shot. Finn recently said that because most younger people right now are about as protected as they can be from severe disease, there is no major benefit in broad distribution of fourth doses.
“I think it’s questionable whether young, healthy people will ever be offered another COVID vaccine beyond dose three – at least with the vaccines and variants we have now,” Finn said to The Guardian. “You just don’t achieve anything very useful by [further] immunizing healthy young people with these vaccines because they rarely get sick – which the vaccines prevent.”
Another wrinkle in the fourth-dose debate is the looming possibility of an Omicron-specific booster. Both Moderna and Pfizer are in the advanced stages of developing a more targeted booster vaccine but it is still unclear exactly when these new shots will arrive.
Both companies have been working on a booster targeting the BA.1 subtype of Omicron. The problem is that recently emerging subvariants of Omicron (BA.2.12.1, BA.4 and BA.5) are suspected to be able to evade immunity generated by a BA.1 infection.
So although Moderna has estimated it could have its new booster ready for distribution from September, that timeframe is based on the presumption that BA.1 is the correct antigen target to shoot for. Some viral evolution experts have recently warned the virus is evolving rapidly at the moment and variant-specific vaccines will be too slow to produce.
Paul Loubet and Idile Launey, vaccine researches in France, suggest we cannot wait until these new variant-specific vaccine formulations appear. They argue vulnerable populations must be given booster shots now to help reduce rates of severe disease over the coming months.
“Heterologous boosters with next-generation vaccines, such as multivalent vaccines (vaccines providing protection against different variants simultaneously), universal coronavirus vaccines, vaccines eliciting stronger T-cell responses, or mucosal vaccines (either intranasal or oral), are among the future options for COVID-19 vaccination,” the pair wrote in a commentary for The Lancet. “However, while awaiting these next-generation vaccines, booster immunizations are crucial to restore vaccine effectiveness against severe outcomes in clinically vulnerable populations.”
The UK 4th dose study was published in The Lancet Infectious Diseases and the Israel 4th dose study was published in The New England Journal of Medicine.
