The coming of the bivalent vaccines, and the need for yearly Covid-19 boosters

CLINICAL MATTERS

As the horrendous Valentine’s Day traffic clearly showed, people are going out once again with a vengeance. Restaurants were full to bursting, and the malls were packed. Yes, the masks are still here (a good thing), but almost everything else is back to normal. The Covid-19 report for Feb. 13, 2023 showed only 91 new cases. The last time the daily count was below 100 was at the start of the pandemic in March 2020. It has been almost three long years since the first lockdown and people are clearly moving on.

The World Health Organization (WHO) in its latest meeting in January 2023 declined to end the pandemic emergency for now. WHO director general Tedros Ghebreyesus said, however, that Covid-19 was certainly well on its way to endemicity. WHO remains concerned about the low vaccination rate in many developing countries, the poor booster uptake worldwide, as well as the continuing emergence of new variants.

There are important scientific questions on how relevant the new bivalent boosters are for the general population, given the continued low mortality even among those who have only received monovalent (old vaccine) boosters. A recent US FDA proposal suggested that updated Covid-19 vaccines be given yearly, like influenza. The scientific community has been divided on this recommendation, stating that Covid-19 does not follow the same seasonal pattern as influenza and it would be difficult to predict what predominant variant will emerge. There remains some uncertainty regarding what clinical benefit a yearly boost will add on top of the first bivalent booster, and whether the bivalent vaccines can be used for primary series vaccination. Finally, there is the question of whether it is necessary to include the original SARS-CoV-2 material in yearly boosters just like in the bivalent formulations, or if the most current variant should be the only one in the updated vaccine.

Scientific recommendations are ideally based on the latest and best quality evidence. During the pandemic, we did not have the luxury of waiting for the most rigorous evidence since these take time to gather and review. Instead, many interim recommendations were formulated based on preliminary data and real-world studies. The risk of waiting for the long-term results of studies instead of acting on initial positive results is substantial, given the clear and present danger of exponential Covid-19 infection. For instance, while randomized, placebo-controlled trials for efficacy of the vaccines were completed at the time of vaccine approval for emergency use, the safety data was only available for these over a few months of observation. Waiting for an entire year to look at long-term safety data when people were already dying from Covid-19 was not practical when it was already clear that these vaccines could save many lives. Since most severe adverse reactions occur in the early part of clinical trials, it was deemed acceptable to use the vaccines once the benefits significantly outweighed the risks. As the vaccines were rolled out, safety data continued to be gathered and monitored. While some unexpected events did occur such as the increased risk of myocarditis from mRNA vaccines in certain age groups and in males, the overall benefit continued to outweigh the risks. Specific to the myocarditis issue, the increased risk of myocarditis from mRNA vaccines even in the most at-risk populations was five to 10 times lower than the risk of myocarditis from Covid-19 infection.

There is no doubt that the effectiveness of primary Covid-19 vaccination in preventing severe disease has been wildly successful. Despite the emergence of the variants of concern, the long-lasting protection of the original monovalent vaccines against hospitalization and death has remained high. It wasn’t until the advent of the Omicron variant that boosters became necessary to top off protection for the general population. For this purpose, the monovalent vaccines initially performed well. In fact, despite the less than stellar uptake of boosters, Covid-19 hospitalizations and deaths remain low and manageable. While bivalent vaccines do offer upgraded protection, it is unlikely that Covid-19 will ever regain its original deadliness even if the uptake is less than optimal since residual immunity against severe disease remains substantial. Given this scenario, yearly updated boosters may only be necessary for the most vulnerable populations, who need the extra protection, while the general population might only need one bivalent booster for now.

As the bivalent boosters arrive in the country, it is prudent to start giving these to the most vulnerable (A2 elderly) and the most exposed (A1 healthcare workers) populations. Because the predominant circulating variants are Omicron sublineages, everyone above 12 years old will likely benefit from getting a bivalent booster regardless of the number of boosters they have previously received. Due to the limited global supply of the bivalent vaccine, the priority groupings should still be followed until the available bivalent vaccine stocks catch up. When the vaccines are given full approval by the FDA, the private sector can also help procure bivalent vaccines to increase coverage among the general public.

Meanwhile, the remaining millions of stocks of monovalent vaccines can be reserved for primary series vaccinations and for the younger age population who are not yet vaccinated or boosted. It is no longer prudent to give monovalent boosters to those 12 years and older since the bivalent boosters seem to work better especially against Omicron. It may be simpler to adopt the US CDC approach, which no longer counts the number of boosters previously received. To simplify the bivalent vaccine rollout, the objective should be to give anyone 12 years old and above one bivalent vaccine dose regardless of the number of booster doses they had previously. Anyone above 12 years old who has not had the primary series should still get the initial two doses with monovalent vaccine followed by one bivalent booster. There is no evidence that two bivalent boosters offer any added protection over one bivalent booster so anyone in the A2 population who has not been boosted will only need one bivalent booster.

Studies using bivalent vaccines as the primary series are ongoing and if it does show efficacy equivalent or better than the monovalent vaccines, there may come a time when all the stocks of vaccines will only be bivalent. Unfortunately, bivalent vaccines are significantly more expensive and harder to produce than monovalent ones currently. Until there is clear evidence that bivalent vaccines are at least equivalent to monovalent vaccines as a primary series, there remains a role for the monovalent vaccine, especially in the younger populations who have not yet been vaccinated. It isn’t a sure thing that bivalent vaccines will do just as well as monovalent vaccines as the primary series due to a phenomenon known as interference or imprinting. This occurs when the antigen response may be blunted when the body has to choose which viral component of the vaccine it will react to. In the case of the bivalent vaccine, the original virus spike protein mRNA and the BA.4/BA.5 spike protein mRNA may end up competing with each other and the resulting response may not be optimal.

One way to mitigate this is to leave out the original virus spike protein mRNA and just produce an updated monovalent vaccine containing the latest circulating variant. These studies are ongoing as well. We continue to learn as we go along and, as in the case throughout the pandemic, it is always prudent to follow the science as it evolves in order to save the greatest number of lives.