With Monday's announcement that the U.S. FDA has expanded emergency use authorization (EUA) for Pfizer and BioNtech's COVID-19 vaccine, Comirnaty (tozinameran), to include adolescents 12 through 15 years of age, and the EMA expected to follow suit in short order, the COVID vaccination campaign is expanding its age range.

Clinical trials for younger children are ongoing. Comirnaty is in trials in children 2 years and older, while Moderna's mRNA-1273 and AstraZeneca's Vaxzevria (AZD-1222) are in trials for infants 6 months and older.

While the expansion of vaccines into younger populations was welcome news and will be important for herd immunity, in some ways, the more urgent question is how to further improve vaccine protection for the elderly, who face a vastly higher risk of severe disease and death upon infection.

At the 2021 virtual annual meeting of the American Association of Immunologists (AAI), researchers shared their insights into optimizing immune responses to vaccines in the elderly.

In a session on "Vaccines and immunotherapy against SARS-CoV-2," Ebony Gary, a postdoctoral scholar at the Wistar Institute, discussed her team's work on using adenosine deaminase (ADA) as a molecular adjuvant to improve immune responses in elderly mice.

Gary and her team are focused on DNA vaccine antigens, which have some of the simplicity advantages of mRNA vaccines, and are shelf-stable for extended periods of time making them "especially suitable for emerging infectious disease work," Gary said. In collaboration with Inovio Pharmaceuticals, the team has developed experimental vaccines for Zika virus, Ebolavirus and the Middle East respiratory syndrome (MERS) coronavirus, as well as a SARS-CoV-2 vaccine that is currently in phase II/III trials.

Adenosine deaminase 1 (ADA-1) is a metabolic enzyme that metabolizes deoxyadenosine, which is toxic to B and T cells. Lack of ADA-1 results in severe immunodeficiency in infants, and the enzyme plays a key role in supporting follicular helper T cells, which support the maturation of antigen-producing B cells. ADA expression naturally declines with age, leading to more plentiful but less effective follicular T-helper cells and weaker immune responses. Gary and her colleagues have previously demonstrated that plasmid-encoded ADA (p-ADA) could improve vaccination-induced responses to HIV.

In her presentation at the AAI meeting, Gary showed data that in aged animals, co-vaccination with DNA antigens to the SARS-CoV-2 spike protein and p-ADA improved immune responses in a way that was "dramatic, and apparent after one immunization," she told the audience.

Compared to mice immunized with DNA vaccine only, co-immunized animals that were 72 weeks old had increased spike-specific IgG antibodies as well as increased T-cell responses after both the first and the second immunizations.

Young animals whose vaccinations were adjuvanted by p-ADA also showed increased immune responses after the first vaccination, but their antigen-only peers caught up after the second vaccination. However, Gina Cusimano, a graduate student at Drexel University College of Medicine, showed that young animals' immune responses to adjuvanted vaccines were more durable. How long-lasting are immune responses to vaccination and infection has been a key question in the fight against COVID-19.

Meanwhile, preclinical research into vaccination of youngsters is also ongoing. Alan Curtis, a postdoctoral scholar at the University of North Carolina at Chapel Hill, reported on the results of vaccinating infant macaques.

Although children rarely suffer from serious bouts of COVID-19 if they get infected with SARS-CoV-2, turning SARS-CoV-2 vaccinations into one more routine childhood vaccination would have several benefits, Curtis told the audience in his talk "SARS-CoV-2 vaccines induce potent immune responses in infant rhesus macaques."

Vaccinating infants could eliminate both severe pediatric disease and transmission from infants to adults, who face a much higher risk of severe disease. Vaccinating infants would also have "the unique advantage of curbing the socioeconomic impact of the pandemic due to school closings, etc.," he said.

In their work, Curtis and his team vaccinated 2-month-old macaques, which is roughly the equivalent of 6 months in human babies. They tested two vaccines, an mRNA vaccine that is "a preclinical cousin" to Moderna's authorized vaccine mRNA-1273 and a stabilized prefusion spike protein vaccine from the NIH's Vaccine Research Center.

Both vaccines, Curtis said, elicited "strong and durable immune responses" in infant rhesus macaques "justifying urgent clinical translation."



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