Vaccine Update and more BA.2

How much is enough?

We have been getting the information for a while now that 2 dose RNA vaccine efficacy has faded over time, but that third doses restore robust protection from severe disease and hospitalization. 90% protection, or something in that range, has been frequently cited. Looking at rising percentages of vaccinated people among the hospitalized over time is misleading since it was inevitable that as more people were vaccinated they would begin to represent a higher proportion in the hospital. Indeed it’s true that if everyone was vaccinated then the only people in the hospital would be the vaccinated, but this not helpful and is misleading. Several days ago the CDC released data in MMWR of a very large study looking critically at the issue of decaying vaccine efficacy over time and spanning both the Delta and Omicron periods. They evaluated both emergency medical visits and hospitalizations in over 300,000 people and the results are neither warm or fuzzy.

Let’s just concentrate on the Omicron data, since that is the only virus that matters now. As expected vaccine efficacy for both 2 and 3 dose regimens was lower in the Omicron than Delta timeframes. 3 doses of vaccine, during the Omicron dominant period, was 87% effective in preventing ER visits during the first 2 months after the third dose, but decreased to 66% for people between 4 -5 months post booster. Vaccine efficacy (VE) against hospitalization was 91% during the first 2 months after a booster, but decreased to only 78% at 4 months. We can reasonably expect this decline in efficacy to continue over time. How do we use this information to maximal personal advantage? For starters we can assume that people who are immunocompromised, or have other clearly recognized risk factors for severe disease, are overrepresented in the hospitalized group. Clearly, they should be considering taking a fourth dose sometime in the near future, particularly if they live or plan to visit a place where disease transmission remains high. Preventing hospitalization is one thing, but I assume that most people would want to avoid getting sick enough to require an emergency room visit. With only a 66% VE of a three dose regimen out beyond 4 months, (and dropping) I think many otherwise healthy people would consider a fourth dose. It certainly is a decision based on weighing your risk tolerance, ongoing mitigation efforts, and the knowledge that in all likelihood the beneficial effects of another dose of vaccine will be transient. Moving on to BA.2, the variant de jour, there is some important information that is rapidly evolving. As discussed in my prior post, this Omicron sub-lineage has rapidly taken over in Denmark and India. It remains a small percentage of viral sequences in the US, but Nowcast data shows that it has doubled once a week for the last 3 weeks. This strongly suggests it is poised to become a much larger amount of the circulating virus in short order. What separates BA.2 from Omicron are 8 unique mutations in the Receptor Binding Domain (RBD), which is the real business end of the virus. As we would expect, it is antigenically quite distinct from Omicron, which raises the issue of antibody escape. A preprint from David Ho’s lab this week looks at the neutralizing effect of 19 monoclonal antibodies (MABs) against the different Omicron sub-lineages. Right now the only available therapeutic MAB with activity against Omicron is sotrovimab and that is in very short supply. As you will recall the virus evolved resistance to both Regeneron and Lilly’s initial combination MAB therapy. Dr. Ho et. al. report that sotrovimab is 27 times less active against BA.2 than it is against Omicron. On the bright side one other MAB they tested, with the catchy name of bebtelovimab, retains good activity against BA.2 and all the Omicrons. This MAB received an EUA on Friday for therapeutic treatment. Unfortunately, since there was no pre-order from the government prior to the EUA this will remain in short supply, like other therapeutics, for several months.