Researchers update the composition of influenza vaccines every six months to match the strains of the virus that are circulating in the wild, so that the shots may provide protective immunity against the flu. But despite their best efforts, researchers rarely perfectly match the strains loaded in the vaccine with the strains circulating by the time the vaccines reach the market.
The reason for this is the long gestation period – usually at least six months – between identifying the circulating strain and the development, manufacturing, and distribution of the vaccines. By the time the updated flu vaccine is available, the circulating strain may have drifted from the one contained in the vaccine, thanks to the high mutational rates of influenza viruses.
The ‘match’ between strains included in the vaccine and strains in circulation is the most important factor controlling the vaccine effectiveness (VE) of flu vaccines. The VE increases by more than 25% when there is a match with the circulating strains but can be as low as 10% in seasons when there is no match.
Another issue with flu vaccines is the durability of protection. According to a recent study, the VE declines by 7% for H3N2 to 11% for H1N1 viruses per month, and could vanish as soon as 90 days after vaccination.
There are some striking similarities between the influenza and COVID-19 vaccines. The VE of COVID-19 vaccines varies according to the disease’s progression as well as the circulating strains. With the advent of the highly mutated Omicron variant of SARS-CoV-2, the VE of COVID-19 vaccines has nose-dived.
According to one large study, COVID-19 vaccines had a VE of 52.8% against the Delta variant but only 16.4% against the Omicron. Another large review – of the findings of 78 studies on the VE of four COVID-19 vaccines before the advent of Omicron – concluded that VE against symptomatic disease waned by 20-30% by the sixth month of the primary series.
Thus, researchers worldwide rushed to revise COVID-19 vaccines that contained the ancestral strain to match the circulating strain of SARS-CoV-2 and keep it clinically relevant.
In early 2023, a highly mutated sub-lineage of the Omicron variant, XBB.1.5, emerged. It was antigenically as distant from the ancestral strain of SARS-CoV-2 as the latter was from the SARS-CoV-1 virus. There were three COVID-19 vaccines available as booster doses at this time: the monovalent ancestral (OG) shot, a bivalent OG+BA.1 shot, and a bivalent OG+BA.5 booster. However, as stated above, none of the vaccines (including mRNA vaccines) were found to be efficacious against infections of this hypermutated variant.
Subsequently, the vaccine was updated in mid-2023 to include the antigens of the XBB.1.5 strain. But by the time the U.S. Centers for Disease Control (CDC) approved and recommended the updated monovalent vaccine as a booster, another new lineage of Omicron, JN.1, had emerged with more than 30 mutations in the spike protein and a high immune-evasion potential. By January 2024, JN.1 had completely replaced XBB.1.5 in the population.
The CDC estimated the updated booster was around 50% efficacious against symptomatic JN.1 infections but some experts doubted this figure.
Merit in updating COVID-19 boosters
The matching problem raises a pertinent question: Is it prudent to attempt frequent updates?
One interesting study from Australia, uploaded as a preprint paper on February 9, analysed this question in detail. Researchers retrospectively analysed 18 studies that investigated the ability of the OG, the OG+BA.1, and the OG+BA.5 boosters to neutralise the variant that started circulating immediately after their deployment. They found that updated vaccines consistently improved neutralising antibody titres by 40% or more compared to non-updated vaccine formulations.
Specifically, the researchers found that relative to the OG antigens’ efficacy against XBB.1.5, the BA.1 update did a better job and the BA.5 update did even better. Based on these benefits in the neutralisation titres, they predicted that updating an existing vaccine should, on average, induce a 1.52-times higher titre against a future variant compared to boosting with an older formulation. The researchers also stated they expect a 11-25% increase in VE against symptomatic disease and 23-33% against severe disease caused by the future variant.
In sum, the study supports the case for revising COVID-19 vaccines’ formulations as often as possible.
However, there are some confounding factors, including past exposure to infections, inter-study variations of such exposures, in vitro and in vivo differences, and publication biases. The researchers also clarified the benefits of the update would depend on the ‘distance’ between the antigens in the updated vaccine and the future variant that eventually circulates. Indeed, there is no guarantee that a profoundly drifted variant with a very high transmissibility and more virulence won’t emerge in future, and which would negate the advantage of updating existing vaccines.
Further, the researchers only explored one arm of the immune system: the humoral immunity conferred by antibodies. The other arm, cellular immunity conferred by T-cells, wasn’t considered. T-cells are like airbags: they deploy on their own and become safer to use with every accident (or exposure) that engineers study. Antibodies are like brakes. Our brain deploys them. They are terrific when new but suffer wear over time, and need to be updated.
Does India need an updated booster?
In India, the advent of Omicron (mainly BA.2) in January 2022 and its resultant mild disease rendered a much lower uptake of COVID-19 vaccines. For many Indians, the pandemic is long past, notwithstanding a few surges in 2023. Currently, there is no Indian vaccine with antigens matching the currently dominant JN.1 strain or its predecessor, XBB.1.5. Corbevax, the vaccine made by Biological E, is currently developing an XBB-based vaccine.
Whether Indians should be boosted with an updated COVID-19 vaccine depends on the objective. If it is to prevent severe disease, hospitalisation, and death, only three exposures – through natural infection or vaccination – will suffice to confer protection irrespective of the antigenic makeup of the circulating variant. (This protection is provided by our T-cells.) This is the case with most healthy, immunocompetent individuals.
For the vulnerable sections of society, like the elderly and those with comorbidities and immunodeficiencies, it is desirable to actively prevent an infection. These individuals need an updated booster. The vaccines based on OG or older strains may not offer meaningful protection owing to the mismatch and other factors.
All available influenza vaccines are being developed on conventional egg-based or cell-culture platforms, which is why updating them takes six months or more. Many COVID-19 vaccines use the mRNA platform whose main attraction is the ease and speed with which they can be modified. Unfortunately, updating mRNA vaccines has also required four to six months.
India also has a next-generation mRNA vaccine called Gemcovac, developed indigenously by Gennova Lab and based on the old Omicron variant. It can also be updated to use a contemporaneous variant, but that depends on the need and the will of the national recommending authority as much as the still-evolving SARS-CoV-2 virus.
Vipin M. Vashishtha is past national convener, IAP Committee on Immunisation, and director, Mangla Hospital & Research Center, Bijnor.
- Researchers update the composition of influenza vaccines every six months to match the strains of the virus that are circulating in the wild, so that the shots may provide protective immunity against the flu.
- But despite their best efforts, researchers rarely perfectly match the strains loaded in the vaccine with the strains circulating by the time the vaccines reach the market.
- The reason for this is the long gestation period between identifying the circulating strain and the development, manufacturing, and distribution of the vaccines.
