From the February 15, 2022 Newsletter; Editor: Alyson Browett, MPH with comment from Michael Lerner

The Johns Hopkins Covid websites and reports are top of their class for straightsummaries of the often confusing news.  I read them all.

Michael Lerner

VACCINE FOR <5 CHILDREN The US FDA on February 11 postponed an advisory committee meeting set for today to discuss data on the Pfizer-BioNTech SARS-CoV-2 vaccine for young children ages 6 months through 4 years. According to an FDA statement, Pfizer notified the agency of new data from an ongoing clinical trial, and the postponement will allow the FDA time to consider that data. As previously reported here, the companies originally tested the vaccine as a 2-dose regimen, with each dose containing 3 μg, one-tenth of the dose given to those ages 12 and older. However, the companies announced late last year that among children aged 2 to 4 years old, 2 doses generated only 60% of the antibody levels seen in individuals aged 16 to 25 years who received 2 doses. Notably, 2 doses did appear to elicit antibody levels among the youngest children aged 6 months to 23 months similar to those in the older individuals. 
The FDA originally pushed Pfizer and BioNTech to request authorization for an initial 2-dose regimen while collecting data on a third dose, but Dr. Peter Marks, Director of the FDA Center for Biologics Evaluation and Research, implied the new data showed that 2 doses were not sufficient in protecting against symptomatic infection, particularly during the latest Omicron surge. Former FDA Administrator and current Pfizer Board Member Dr. Scott Gottlieb said the delay was due to a “low number of cases” in the trial, perhaps insufficient for data analysis. The companies expect data on the 3-dose regimen to be available in early April
Efforts last week by the US CDC to open preordering of the vaccine indicated the decision to authorize a 2-dose regimen while waiting on further data on 3 doses was nearly a done deal, with the agency predicting shipments of the lower-dose version could begin the week of February 21. While some experts breathed a sigh of relief that the FDA is taking extra time to review the scientific evidence, some parents expressed dismay and frustration over what they say feels like a string of setbacks. Still, not all parents are eager to vaccinate their younger children. The Pfizer-BioNTech vaccine has been available for children aged 5 to 11 since early November 2021, yet only about one third of the 28 million children in that age group have received at least 1 dose so far. A recent survey from the Kaiser Family Foundation showed about 30% of parents of children younger than age 5 intend to get them vaccinated as soon as shots become available. Approximately 400 children under age 5 have died of COVID-19 since the beginning of the pandemic.

BOOSTER DOSE EFFECTIVENESS Booster doses of SARS-CoV-2 mRNA vaccines are strongly recommended by public health and medical professionals—even more so during the recent surge in cases caused by the Omicron variant of concern—to lower the risk of symptomatic COVID-19 and more severe cases requiring hospitalization. Emerging data continue to support booster doses as both safe and effective for these purposes. A recent study published in the US CDC’s Morbidity and Mortality Weekly Report (MMWR) found that vaccine effectiveness at preventing severe COVID-19 was higher after a booster dose than after the second dose of mRNA vaccine. The effectiveness of boosters wanes after about 4 months but remains highly protective against severe disease. These findings were consistent across both the Delta-dominant and Omicron-dominant periods. The findings support further consideration of additional booster doses that could be valuable against future outbreaks or variants. 
Despite booster doses being highly effective in preventing emergency department visits and hospitalizations due to COVID-19, public uptake of booster doses has slowed in recent months in the US. A survey from the Kaiser Family Foundation found that 60% of vaccinated but not boosted respondents stated that the Omicron wave did not greatly impact their decision whether or not to get a booster. Only around 29% of respondents reported that the Omicron wave made them more likely to get a booster shot. Additional data from the CDC on hospitalizations and deaths show that booster doses are most beneficial to older adults. The argument for booster doses is strongest in those aged 65 years and older, for whom booster doses reduced the death rate per 100,000 cases by around 90 times. More work still needs to be done to better understand the durability of immunity following booster doses as well as to encourage more people, particularly those in higher-risk populations, to receive their booster doses.

COVID-19 THERAPEUTICS Late last week, the US FDA authorized a new monoclonal antibody (mAb) treatment that reportedly retains activity against the SARS-CoV-2 Omicron variant in laboratory experiments. The treatment—known as bebtelovimab and made by Eli Lilly—received Emergency Use Authorization (EUA) for adults and certain pediatric patients who are at high risk of severe COVID-19 outcomes but was not authorized for hospitalized COVID-19 patients or those requiring supplemental oxygen. Eli Lilly has signed a contract with the US government to supply up to 600,000 doses of the treatment by March 31, with the option for an additional 500,000 doses to be delivered later this year, at a cost of at least US$720 million. The company said it will immediately begin shipments to fulfill the agreement. Many providers expressed gratitude for the authorization, after the US government halted the use of 2 of the most common monoclonal antibody treatments due to a loss of effectiveness against Omicron. 
Also late last week, the WHO prequalified a different mAb treatment, tocilizumab, that inhibits the interleukin-6 (IL-6) receptor. The prequalification includes 3 different presentations of the treatment and represents the first mAb to receive the designation. Tocilizumab—which is used primarily to manage arthritis and has been the subject of many COVID-19 clinical trials, including the large RECOVERY trial—is prequalified only for patients diagnosed with severe or critical COVID-19. The RECOVERY trial continues its work to establish an empirical baseline of effectiveness for other therapeutics. In a study published February 12 in The Lancet, the RECOVERY Collaborative Group summarized the results of evaluation of the monoclonal antibodies casirivimab and imdevimab used in combination. Between September 2020 and May 2021, the combination treatment reduced 28-day mortality in patients who were seronegative at baseline—meaning they had not mounted their own immune response—but not among individuals who were seropositive at baseline. However, when all patients were considered together, the treatments had no significant difference in outcomes. The results support the use of the combination therapy only among hospitalized individuals who are seronegative.
Questions remain over how well mAb treatments work against Omicron, as well as its BA.2 sublineage. Vir, the producer of the mAb sotrovimab, published a press release last week stating that its treatment retains neutralizing activity against the BA.2 sublineage of Omicron. The laboratory data, which are expected to be posted to a preprint server this week, are not yet peer-reviewed. Conversely, a separate study posted to bioRxiv (also not yet peer-reviewed) found BA.2 exhibited resistance to sotrovimab. Other therapies, including the antivirals Paxlovid and remdesivir, remain effective at reducing the risk of COVID-19-associated hospitalization or severe disease, but supply constraints and administration challenges are limiting access to only the highest-risk patients. 

US VACCINE MANDATES New York City last week fired 1,430 municipal employees—less than 1% of the city’s workforce—for not complying with the city’s SARS-CoV-2 vaccination mandate. About 95% of the city’s 370,000 workers have received at least 1 dose of vaccine. Approximately 9,000 workers remain unvaccinated and are seeking exemptions but still could face termination. A majority of the fired employees, about 900, worked at the Department of Education. On February 11, the US Supreme Court denied a request from a group of New York City public school teachers, administrators, and staff seeking to block the mandate for employees who were not granted religious exemption. Those involved in the lawsuit were told they would be fired if they did not get vaccinated by February 14. 
In compliance with the US Department of Defense vaccine mandate for military personnel, the US Navy and US Army announced they have begun discharging unvaccinated soldiers. The US Air Force last week said it has granted 9 religious exemptions and continues to process 2,556 pending requests and 732 pending appeals. Overall, the Air Force has turned down more than 3,200 requests for exemptions and approximately 440 appeals. The US Navy has not yet granted any religious exemptions.

CANADIAN PROTESTS After being closed for nearly a week because of demonstrations against COVID-19 vaccine mandates and restrictions, the Ambassador Bridge—the busiest US-Canada border crossing—reopened late February 13 after police made more than 2 dozen arrests, towed 7 vehicles, and seized 5 others. The bridge, which links Ontario to Detroit, is a major artery for the transport of vehicle parts from Canada to automotive plants in the US. Protests continue to block border crossings between Emerson, Manitoba, and Pembina, North Dakota, and Coutts, Alberta, and Sweet Grass, Montana. Additionally, demonstrations that began January 29 continue in the Canadian capital of Ottawa, disrupting transportation and daily activity. On February 14, Canada Prime Minister Justin Trudeau announced he is invoking the Emergencies Act, allowing the government the authority to “restore order.” The unusual move is meant to counter acts of lawlessness seen during the protests, according to Canada Public Safety Minister Marco Mendicino, who called the move “very careful and deliberate.”  
Earlier on February 14, TD Bank—short for Toronto-Dominion Bank—froze approximately US$1.1 million that was intended to go to groups supporting the “Freedom Convoy” leading the Ottawa demonstrations, most of which came from a GoFundMe account that was shut down. TD Bank has said it wants the courts to decide where the money should go. After the GoFundMe account was shuttered, a crowdsourcing site on GiveSendGo began to raise money. Late last week, an Ontario Superior Court decision to grant the Canadian government authority to freeze access to any money raised to back the blockade. Meanwhile, GiveSendGo said it could continue to deliver money to protestors, but the site was hacked late on February 13, with hackers releasing the names of donors. Also on February 14, Ontario Premier Doug Ford announced the province will no longer require proof of vaccination to enter indoor spaces as of March 1 due to a decreasing number of COVID-19 cases and hospitalizations. He clarified that the restrictions were not being lifted in response to the demonstrations. 

ASIA Several nations and regions in Asia have experienced increases in new COVID-19 cases following Lunar New Year celebrations held early this month, with governments grappling with how to respond to the Omicron variant that has found its way through strict border controls. Hong Kong is experiencing a record surge in cases, reporting more than 2,000 new cases on February 14. The outbreak is overwhelming hospitals, forcing schools to remain closed, and necessitating help from China to address what Hong Kong Chief Executive Carrie Lam called an “aggravating situation.” Hong Kong has been following the mainland’s zero-COVID strategy by isolating all patients in hospitals to suppress transmission, but this outbreak is testing the limits of that policy. For now, there are no plans for a strict lockdown in Hong Kong, although a more-intrusive contact-tracing app is being used to restrict the movements of unvaccinated individuals. 
China is continuing to enforce its zero-COVID policy, shutting down entire cities and holding the Beijing Winter Olympics in a strict “closed-loop” bubble that some have criticized as excessive. A paper published last week in the weekly bulletin of the China Center for Disease Control and Prevention (CCDC) estimated that if the global vaccination rate was 95% and population mobility returned to 2019 levels, zero-COVID regions would see more than 234 million new cases in 1 year, including 2 million deaths. Without the development of more effective and durable vaccines, a constellation of public health mitigation measures will need to be continued to stave off further crises, although most experts agree that China’s widespread lockdowns are extreme.

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