The Science Supporting the U.S. Case for COVID Boosters

U.S. health officials laid out the scientific rationale for a third dose of the COVID-19 mRNA vaccines for all U.S. adults on Wednesday, relying on published and unpublished CDC data, as well as a preprint study.

Overall, they said that there is evidence that vaccine effectiveness against infection — both symptomatic and asymptomatic — has been decreasing over time, but that protection against severe disease, hospitalization, and death remains relatively high.

In anticipation of further waning of immunity amid the ongoing Delta variant-fueled surge — which is posing additional challenges — pulling the trigger on booster shots could help the U.S. stay ahead of the virus, they said.

During a White House COVID-19 task force briefing, CDC Director Rochelle Walensky, MD, offered five pieces of evidence to support the move: three new studies that were published Wednesday in the Morbidity and Mortality Weekly Report (MMWR), one previously published on medRxiv, and unpublished CDC data on the Delta variant.

Protection Against Infection

Walensky cited new MMWR data from New York that showed a decline in vaccine effectiveness against infection, from 91.7% to 79.8% during the period of May 3 to July 25.

Eli Rosenberg, PhD, of the New York State Department of Health, and colleagues linked data from several New York surveillance systems on immunization, lab testing, and hospitalization.

During that time period, they found that a total of 9,675 new cases of COVID-19 occurred among fully vaccinated adults compared with 38,505 cases among unvaccinated adults (1.31 vs 10.69 per 100,000 person-days).

In addition, data from the Mayo Clinic, published previously on medRxiv, similarly found a decrease in vaccine efficacy in preventing infection in Minnesota, Walensky said. For the Moderna vaccine, effectiveness against infection fell from 86% in January-July, down to 76% during the month of July, while it fell from 76% down to 42% for Pfizer during that time.

Finally, new data from MMWR from a national network of nursing homes showed a reduction in protection against infection, from 75% in March to 53% as of August 1, Walensky said.

Srinivas Nanduri, MD, of the CDC, and colleagues assessed weekly data on nursing homes and skilled nursing facilities reported by CMS to the CDC’s National Healthcare Safety Network.

They found that the adjusted effectiveness against infection during the “pre-Delta” period (March 1 to May 9) was 74.7% (based on 17,407 weekly reports from 3,862 facilities), which fell to 67.5% in the “intermediate” period (May 10 to June 20; based on 33,160 weekly reports from 11,581 facilities), and ultimately to 53.1% during the Delta dominant period (June 21 to August 1; based on 85,593 weekly reports from 14,917 facilities).

Nanduri and colleagues noted that estimates of effectiveness were similar for both vaccines.

“Taken together, you can see that while the exact percentage of vaccine efficacy differs depending on the cohort and setting studied, the data consistently demonstrate a reduction in protection from infection over time,” Walensky said.

Protection Against Severe Illness and Hospitalization

Walensky noted that despite the waning in efficacy against infection, data suggest that the vaccines are still highly protective against severe illness and hospitalization.

The New York MMWR data showed that from May 3 to July 25, the overall age-adjusted vaccine effectiveness against hospitalization was relatively stable (91.9% to 95.3%).

Additionally, there were a total of 1,271 new hospitalizations among fully vaccinated people, compared with 7,308 hospitalizations among the unvaccinated (0.17 vs 2.03 per 100,000 person-days), Rosenberg and colleagues reported.

Hospitalization rates declined through the week of July 5, but increased during the weeks of July 12 and July 19, they added. Hospitalization rates were also higher among those 65 and up, they found.

The Mayo Clinic preprint found that from January to July in Minnesota, both the Moderna and Pfizer vaccines were effective at protecting against COVID-associated hospitalization (91.6% vs 85%, respectively) and ICU admission (93.3% vs 87%, respectively). There were no deaths in either cohort.

Finally, new MMWR data from CDC’s IVY (Influenza and Other Viruses in the Acutely Ill) Network reported by Mark Tenforde, MD, PhD, of the CDC, and colleagues showed no decline in vaccine efficacy against hospitalization over 24 weeks — though Walensky noted that the cohort was short on Delta infections.

The authors assessed IVY-collected data on 3,089 hospitalized adults from 21 hospitals in 18 states from March 11 to July 14. Of these, 1,194 were COVID-19 patients and 1,895 were controls who didn’t have COVID-19. Overall, 11.8% of cases were fully vaccinated, as were 52.1% of controls.

The efficacy rate against hospitalization was 86% overall and 90% among adults without immunocompromising conditions, they reported.

Additionally, of the 1,129 patients who’d received two doses of an mRNA vaccine, there was no decline in efficacy against hospitalization during a 24-week period, with an efficacy rate of 86% from 2 to 12 weeks after vaccination compared with 84% at 13 to 24 weeks post vaccination.

However, of the 454 samples that had whole genome sequencing, just 16.3% turned out to be the Delta variant, which now accounts for the vast majority of cases. More than half (53.3%) were of the Alpha lineage.

“Taken together, these data confirm that while protection against infection may decrease over time, protection against severe disease and hospitalization is currently holding up pretty well,” Walensky said. “As we make decisions about boosters, though, we also have to look at vaccine efficacy in the specific context of the Delta variant.”

Double Whammy: Waning Immunity and Delta

Walensky then highlighted preliminary unpublished data from two of the CDC’s vaccine effectiveness cohorts that included more than 4,000 healthcare workers, first responders, and other frontline workers from eight locations across the U.S.

Data through August 6 showed waning effectiveness against symptomatic and asymptomatic infection in the context of the Delta variant, from 92% prior to Delta, to 64% with Delta.

She noted that the analysis didn’t show differences over time, which suggests that vaccine efficacy is diminished against Delta independent of when a person was vaccinated — meaning full vaccination may be less effective against Delta than against previous variants, she said.

Immunological Basis for Boosters

Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, provided the immunological evidence supporting the case for a third shot during the briefing.

Antibody levels decline over time, he said, but mRNA booster shots would increase antibody titers by at least 10-fold.

Higher levels of antibodies are associated with better vaccine effectiveness and are likely required to protect against the Delta variant, he noted.

A paper published in Science showed that antibody levels peaked around 43 days after the second dose of Moderna, but fell by 209 days regardless of the variant involved.

Additionally, a preprint published in medRxiv based on phase III data from the Moderna trial looked at “correlates of immunity,” finding that a serum neutralizing titer of 1:100 produces a vaccine efficacy rate of 91%. Thus, the higher the neutralizing titer, the higher the efficacy of the vaccine, Fauci explained.

The Science paper, as well as Pfizer data published in the New England Journal of Medicine, showed diminished levels of neutralizing antibody titers with Delta compared with other variants, Fauci noted.

Finally, another medRxiv preprint showed that a third dose of Moderna increased antibody titers at least 10-fold, he said, and Pfizer recently announced similar data.

The Moderna study showed a “remarkable increase in titers” 15 days after the third dose against wild-type virus, the Beta variant, and the Gamma variant, Fauci said, adding that Pfizer data also showed a good boost in levels against the Delta variant, which is expected to be similar for Moderna.

“All of this supports the use of a third booster mRNA immunization to increase the overall level of protection,” Fauci concluded.