July 2022 Update on Vaccines
New Covid-19 Vaccine Formulations are Coming in the Fall
The “bivalent” mRNA boosters to be produced by Pfizer/BioNTech and Moderna will include both their current formulations and a component that targets the newly dominant BA.4/BA.5 Omicron sub-variants.
What exactly did the FDA recommend?
On June 28, the Vaccines and Related Biological Products Advisory Committee (VRBPAC), voted 19 to 2 for an Omicron-containing booster in the fall
The committee considered data presented by the CDC, FDA, WHO, Pfizer, Moderna, and Novavax.
The FDA has asked Pfizer/BioNTech and Moderna to develop bivalent boosters that target both the BA.4 and BA.5 subvariants and the ancestral virus.
The new shots should be available in early-to-mid-fall of this year.
Specific recommendations regarding booster eligibility remain to be determined.
Why do we need a reformulated vaccine?
The expectation is that it will provide broader protection from current and future variants that are genetically less similar to the original.
“Antigenic drift” describes how far a virus “drifts” from the ancestral virus (i.e., the so-called “Wuhan” strain) by mutating into a new variant or subvariant.
As shown on the antigenic map below, Omicron is much further from the ancestral virus than Alpha, Beta, or Delta—if Delta is a brother to Wuhan, Omicron is a distant cousin. Continued drift in the form of future variants would attenuate the efficacy of the current vaccines even more.
From: WHO Technical Advisory Group on COVID-19 Vaccine Composition (TAG-CO-VAC)
The subvariants of Omicron are relatively antigenically distant from one another as well.
In just 7 months, the US has cycled through several Omicron sub-lineages as the dominant variant—BA.1, BA.2, BA. 2.12.1, and now BA.4 and BA.5, the latter of which originated in South Africa in February and began dominating most of Europe by mid June.
Europe is seeing a significant surge in cases and the US is likely just weeks behind. By the end of July, it is very likely that the United States will be fully engulfed in a BA.4/5 surge.
What can we expect from the updated vaccine?
A level of protection that is a bit more durable and better at protecting against both infection and severe disease.
What don’t we know about the new vaccine formulations?
Will they prevent infections and long-term issues related to Covid? There is no clinical standard for determining if you are fully protected from an infection, so we won’t know just how well the new vaccines will perform until they are in wide use.
A better measure of protection against severe disease would be if we could develop a standard measurement threshold for T-cell immunity, which is the immune system’s primary tool to protect from severe illness.
Should I care if I get infected if I am keeping up with my vaccination boosters?
According to the CDC, 20-25% of those infected with Covid-19 develop long Covid and the overall risk of respiratory conditions or pulmonary embolism (PE) doubles in those who have had Covid.
We don’t know how new variants compare to older variants in terms of the relative risk of long-term complications from Covid-19 infection, nor how the risks change with multiple infections.
Though the risks are reduced in vaccinated individuals, they remain significant.
Is Omicron inherently less severe for both the vaccinated and unvaccinated?
An overall decrease in deaths seen since March 2022 has been seen. This is perhaps because of the amount of natural infection protection in the community, as well as protection from vaccines and less severe variants.
Hospitalizations were higher among the unvaccinated even after Omicron became dominant.
While it is believed that BA.1 was less severe than Delta, the relative severity of BA.4 and BA.5 are not yet known.
How much protection do you get from a breakthrough Covid infection after a booster?
The combination of a natural “breakthrough” infection plus vaccination/boosters provided the best protection against infection and severe illness. But we don’t know the durability of this kind of immunity.
How vulnerable is the US population?
Since only about half of Americans have been fully vaccinated and single boosted, there is fear that a lack of uptick of first and second booster shots—coupled with the abandonment of mitigation tactics (wearing only high quality and well-fitting masks, social distancing, and avoiding crowded indoor settings)—will leave the population much more vulnerable to bad outcomes as we move into the fall.
What do the data say about the effectiveness of vaccines now?
In May, 2022, unvaccinated individuals over 12 years of age were 8 times as likely to die vs those who were boosted. Those who had been double-boosted were 42 times less likely to die than the unvaccinated and 4 times less likely to die than those with one booster.
Unvaccinated adults who become infected are 3.5 times as likely to go to hospital vs those who were vaccinated without a booster.
Despite protection from severe disease, vaccine effectiveness at preventing infection waned to below 20% in boosted individuals who hadn’t received a shot for at least 150 days during the BA.2 and BA2.12.1. surges.
75% of those who are vaccinated and still develop severe disease are older and with underlying conditions.
How effective can we expect the new vaccines to be?
Both Moderna and Pfizer showed that the bivalent vaccines containing an Omicron component significantly improved neutralizing antibody titres compared to current vaccines.
Pfizer provided brand new information from animal studies showing that their BA.4/5 monovalent vaccine had an 11.3-fold increase in neutralizing antibody titres against the BA.4/5 strain versus the BA.1 monovalent vaccine. These data were paramount in swaying the FDA to recommend a BA.4/BA.5 component to the next generation of boosters.
What is the timeline for rolling out new vaccine boosters?
Now that the recommendations have been made by the FDA, the manufacturers estimate that it will be about 3 months until they have product, although it may take a bit longer to ramp up to meet demand.
What vaccine should be used for the unvaccinated?
The committee largely agreed that the current vaccine formulation should continue to be used for the primary 2-shot series of mRNA vaccines and that the new formulation could then be used for booster doses.
If Novavax is approved for emergency use, it could provide another option as either a primary series or booster.
Will the new vaccine formulations lead more people to get vaccinated or boosted?
It is believed that at this time vaccination status is a personal preference issue, not an access issue.
It is possible that the EUA of the Novavax vaccine will cause some individuals to get vaccinated since the technology is older and has been used for many years.
The new mRNA vaccine formulations may influence people who are not boosted to get the shot in the fall since they are more targeted to the circulating variants.
What We Still Need to Know Going Forward:
How will the increase in neutralizing antibody titres translate to protection in the clinical setting?
How and when will these new booster formulations be rolled out to pediatric populations?
Will the Novavax recombinant full-length spike protein vaccine receive EUA soon and how will it be incorporated into the vaccine armamentarium?
Will the use of “mix-and-match” vaccine protocols prove beneficial? This question is still being studied.
Will intranasal and universal vaccines prove effective in clinical trials at providing better and broader protection against infection? If so, when can we expect these to be available?
Key Takeaways:
Current vaccines are preventing severe disease but are less successful at preventing infection. The effectiveness at preventing severe disease wanes with time and in the face of new variants.
Antigenic drift is expected to continue and a bivalent Wuhan/Omicron BA.4/5 vaccine may provide the best chance for broad protection against future variants
We do not know how the virus will evolve so this decision is based on the scientific community’s general consensus about what is most likely to occur. There are no guarantees, however.
The next generation of boosters should be available before November
In the meantime, first or second boosters of the current formulation still provide significant additional protection against severe disease, especially in those over 60 and the immunocompromised.
Long-term effects from Covid remains a major concern and only time will tell whether these effects become rarer or more muted as the virus evolves and as vaccines are updated. We will also learn whether multiple infections significantly increase long-term complications.