A Complex Calculus - BA.4/5 Component Planned for Fall Booster Shots

The FDA recently announced that it will ask manufacturers to include an Omicron-specific BA.4/5 component in a booster update for the fall. However, it is not yet clear whether a boost in neutralizing antibodies will do a better job preventing death and severe disease than the original strain.

Dr. Paul Offit, one of the vaccine experts who voted “no” to updating the formulation with an Omicron component, expressed doubts in a recent opinion article about the real-world clinical benefits of modifying the vaccine given the tremendous costs associated with research and development. As we develop expectations about the advantages of reformulating the booster, it is important to consider the evidence for current recommendations, which vary internationally.

The European CDC and Australia have expanded their age categories for a second booster dose. Now a second booster is recommended by the ECDC for people ages 60-79 in addition to those 80 years and older as well as high risk people of all ages, partially aligning with CDC’s recommendation for ages 50 and older. Like the CDC, Australia recommends a second booster for those age 50 and older, but went a step further allowing those over 30 to get a second booster if desired. Where does this leave healthy US citizens between 30 and 60 given the diverging international recommendations?

The CDC recently released data on vaccine effectiveness against hospitalization during the Omicron period. A third dose among 18-49-year-olds during BA.1 increased protection from 52% (after dose 2) to 94% (after dose 3). For those over 50, a fourth dose during BA.2 increased protection from 55% (after dose 3) to 80% (after dose 4). However, this data is limited in follow-up duration and may be seriously confounded by comparing the boosted population to those unvaccinated who have immunity from prior infection. In February 2022, 57% of the adult population had antibodies to Covid. Although unvaccinated people with prior infection were excluded from the study, a large number of infections are not reported and thus could not be pulled out of the data. Therefore, it is not yet clear what additional benefit is provided by boosting those who have already recovered from SARS-CoV-2 infection.

Another challenge to modeling the benefit of updating the vaccine is measuring severe illness. A greater proportion of hospitalizations are now associated with but not caused by Omicron infection. In a statement released Monday (July 18) by Los Angeles County: “At the current time, approximately 10% of patients admitted to LAC+USC Medical Center with a positive COVID Test are admitted due to illness caused by COVID.”

Although boosting may transiently improve protection, it does not appear to clear the virus faster, and infection rates seem to be higher among those who have been boosted compared to those who completed only the primary series in CDC’s Covid Tracker. These data may, again, be confounded by the protection conferred by recovering from infection. So far, the best data available were unable to detect a benefit of boosting to prevent severe disease among those younger than 40 years of age. The recent WHO guidance supports this view, stating that “there is no clear evidence to support giving a second booster dose to people below 60 years of age who are not at higher risk of severe disease.”

Building an immunity portfolio

Both infection and vaccination train the immune system to fight SARS-Cov-2, and most of us have had both by now. When the amount of time since the last immune event (whether infection or vaccination) is taken into consideration, infection rates during the Delta wave were similarly low among those who had recovered, regardless of whether they received a dose of vaccine or not. Six to eight months after the last immune activation, infection rates among the fully vaccinated were more than 6 times higher than those with natural immunity alone (88.9 vs 14.0 per 100,000 person-days at risk). A CDC study presenting data from California and New York during the Delta wave found identical results with respect to both symptomatic illness and hospitalization.

Then, during the Omicron wave, these findings were supported with new data. Researchers in Qatar concluded that “no discernable differences in protection against symptomatic BA.1 and BA.2 infection were seen with previous infection, vaccination, and hybrid immunity.” People with a history of infection more than 12 months prior had 54.9% vaccine effectiveness against any symptomatic Omicron infection compared to 44.7% protection among those with a Pfizer booster (third dose) just a month prior. Results for Moderna were similar.

How can infection outperform vaccination? Our immune system is complex and we do not yet have a metric which tells us precisely when the immune-building process is done. In other words, we do not know if a specific antibody level is protective. Vaccination delivers a precise dose of antigen to trigger antibody production, but exposures to the virus itself can be highly variable. Other components of the immune system, such as T and B cells, may be equally or perhaps even more important than the level of neutralizing antibodies. In addition, infection induces a protective layer of antibodies lining the mucus membranes of the airways. This is why a nasal (vs. intramuscular) vaccine would be very helpful. Further, a person’s risk depends on their age, underlying health conditions, the amount of virus in circulation, the time since last immune activation and the next variant’s ability to evade antibodies.

The benefit-risk calculus of boosting with a fourth dose may be most clear for older individuals, half of whom have three or more chronic conditions to manage. In a Swedish study of all-cause mortality among those 80 years or older, the added protection from a fourth dose compared to those with three doses was 71% for two months, then declined to 54% between 2 and 4 months post-vaccination.

Fortunately, most people have enough neutralizing antibodies from vaccination or infection to strongly protect them against severe disease and death—that key task requires immune memory cells and lower neutralizing antibody levels than are needed to completely fend off the virus. A sustainable vaccination strategy at this stage of the pandemic means vaccinating high risk people who are not yet immune, and boosting those with a weakened immune system. High risk patients can further reduce risk with an additional booster and access to rapid testing, monoclonal antibodies and therapeutics in the event of infection. The next generation of vaccines will be targeting new delivery approaches, such as a nasal vaccine to fend off infection by lining the airways with antibodies.


COVID-19 Vaccine Boosters | CDC

TWiV 917: Boosters on, Paul Offit (microbe.tv)

FDA: Don't rush into changing Covid-19 vaccine composition - STAT (statnews.com)

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