Could a single-dose vaccine strategy be more beneficial in COVID-19?

On Monday, the FDA issued a statement reminding the public of the importance of following COVID-19 vaccine dosing schedules currently authorized by the agency.

According to the FDA, the announcement followed public discussions on changing vaccine strategies, including reducing the number of doses, lengthening the time between doses and changing the doses.

In the statement, FDA Commissioner Stephen M. Hahn, MD, and Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research, said that these types of changes are reasonable to consider for evaluation in clinical trials, but currently, there is no evidence to support changes to COVID-19 vaccine doses and scheduling.

“Without appropriate data supporting such changes in vaccine administration, we run a significant risk of placing public health at risk, undermining the historic vaccination efforts to protect the population from COVID-19,” they wrote.

Currently, the approved interval between the first and second doses authorized by the FDA is 21 days for the Pfizer-BioNTech vaccine and 28 days for the Moderna vaccine.

However, a series of papers published in the Annals of Internal Medicine suggest that changing current vaccination strategies may be beneficial to public health.

The FDA did not immediately respond to a request to comment on whether this research was considered in their recommendation.

Speed vs. efficacy tradeoffs

A. David Paltiel, PhD, professor of public health and management at the Yale School of Public Health, and colleagues used a previously published model to evaluate speed vs. efficacy tradeoffs in COVID-19 vaccination.

“Consistent with the FDA efficacy definition, we assumed that a two-dose vaccine produced a 95% decrease in rates of progression to symptomatic disease, to severe or critical disease from mild disease, and to COVID-19-related death, as well as a nearly three-fold increase in rates of disease recovery,” they wrote, adding that they also assumed that the vaccine had a 0.5% daily uptake and took 4 weeks to establish lifetime protection.

The researchers compared the vaccine with two hypothetical single-dose COVID-19 vaccines, one that had lifetime protection and another that had stable efficacy but for an uncertain duration. In the model, both single-dose vaccines were assumed to have a 0.75% daily uptake and to take effect 14 days after vaccination. The researchers considered efficacies for these vaccines ranging from 0% to 100%. They used an effective reproduction number (R_t) of 1.8 in base analyses.

In their model, the researchers determined that a single-dose vaccine with that conferred lifetime protection would only need 55% efficacy to avoid as many infections as two-dose vaccines with 95% efficacy.

However, according to the researchers, a single-dose vaccine with uncertain protection duration would need to achieve 75% efficacy to avoid the same number of infections.

When they analyzed more severe pandemic conditions, with an R_t of 2.1, they found that a single dose conveying lifetime protection needed 50% efficacy and dose with uncertain protection duration needed 70% efficacy to prevent the same amount of infections as a 2-dose vaccine.

“This suggests that now that a highly effective, two-dose vaccine for COVID-19 has been authorized and vaccination programs have begun, sustained and aggressive investment in pursuit of faster-acting, more convenient, one-dose vaccine candidates remains justified,” Paltiel and colleagues wrote.

Maximizing the benefits of each dose

In an Ideas and Opinions article, Ruanne V. Barnabas, MBChB, MSc, DPhil, associate professor in global health and medicine at the University of Washington and the Fred Hutchinson Cancer Research Center, and Anna Wald, MD, MPH, professor and head of the allergy and infectious diseases division at the University of Washington School of Medicine, proposed a plan for COVID-19 vaccine distribution that would maximize the health benefits for each dose of the vaccine.

They noted that both the Pfizer and Moderna vaccines have demonstrated efficacy in COVID-19 prevention after the first dose of the vaccine but before the second in both, with a small group of participants showing an efficacy of 52% after the first dose of the Pfizer vaccine and an efficacy of 51% at 14 days in the Moderna vaccine.

“Currently, 3 million doses of vaccine are being shipped throughout the United States, with an equal number being held back to maintain sufficient supply for the second dose,” they wrote. “We propose that priority should be given to providing a single dose to as many people as possible, rather than emphasizing the two-dose vaccination.”

Barnabas and Wald noted that single-dose COVID-19 vaccination would help accelerate pandemic control, as vaccine coverage would be doubled using a single dose vaccine rather than a two-dose regimen. This is because, they said, even a lack of complete protection from a vaccine could lower effective reproductive numbers enough to stop endemic growth.

Additionally, they wrote that a single-dose strategy that provides effective protection to as many people as possible as soon as possible is more ethical, as it makes distribution more just.

Barnabas and Wald said that a single-dose strategy could also help mitigate the adverse events — such as fever, headaches, chills and fatigue — which have been reported at higher rates with the second dose of both vaccines.

Finally, their rationale for using a single-dose vaccination strategy stems from concern that individuals will stop using infection prevention efforts like masking and physical distancing after being vaccinated. They wrote that a vaccine strategy that only provides partial protection “may ensure continued adherence to other mitigation strategies that will continue to be critical for many months to come.”

Alternative dose allocation strategy

Ashleigh R. Tuite, PhD, MPH, an infectious disease epidemiologist and mathematical modeler at the University of Toronto, and colleagues wrote that as COVID-19 cases rise, “there are important trade-offs to consider between the health costs of deferring benefits of earlier protection for half of people who could be vaccinated from initial supply, weighed against risks of possible vaccine supply disruptions that could delay receipt of second doses in the absence of sufficient reserves.”

Tuite and colleagues developed a model that was designed to estimate the benefits of alternative COVID-19 vaccination strategies. Using the model, the researchers evaluated a fixed strategy based on the current strategy, with 50% of doses for each vaccine reserved for second doses to be administered 3 weeks later. They also evaluated a flexible strategy in which 10% of the vaccine supply was reserved for second doses during the first 3 weeks of vaccination, 90% of the supply over the next 3 weeks was reserved for second doses, and 50% of the supply was reserved moving forward.

They based vaccine characteristics in the model after the Pfizer vaccine. The model assumed efficacy decreased when individuals did not receive the second dose within 3 weeks.

With a steady supply of 6 million doses per week, Tuite and colleagues determined that the flexible allocation strategy would result in 23% to 29% more COVID-19 cases averted than the fixed strategy.

They determined that both scenarios result in 24 million people receiving the first dose by 8 weeks, but the flexible scenario led to an additional 2.4 million people who received two doses. In this scenario, all second doses were provided on time.

Tuite and colleagues found that if the supply dropped to 3 million doses each week at week 4, the benefits of both strategies decreased. In the fixed stratify, they found that 16.5 million people received at least one dose by 8 weeks, 12 million received two doses by 8 weeks, and 12 million received two doses on schedule by 8 weeks. In the flexible strategy, 20.1 million received at least one dose in the first week, 12.9 million received two doses by 8 weeks, and 6.3 million received two doses on time in 8 weeks.

They determined that with a moderate reduction in the vaccine supply, the flexible strategy led to 27% to 32% more COVID-19 cases averted than the fixed strategy overall.

In scenarios with larger declines in vaccine supply and with greater waning of protection if the second dose was delayed, the number of fully vaccinated people decreased. However, the flexible strategy still demonstrated greater benefits compared with the fixed strategy.

“We find that under most plausible scenarios, a more balanced approach that withholds fewer doses during early distribution in order to vaccinate more people as soon as possible could substantially increase the benefits of vaccines, while enabling most recipients to receive second doses on schedule,” Tuite and colleagues wrote.

Considering single-dose strategies

In an editorial published alongside the study, Thomas J. Bollyky, JD, director of the global health program and senior fellow for global health, economics and development at the Council on Foreign Relations, wrote that “in a public health emergency, a powerful argument exists for doing something with less-than-perfect results if it can help more persons quickly.”

“However, whether alternative approaches with current vaccines would accomplish this goal is far from clear,” he added.

Bollyky also said there are multiple barriers to vaccinating those who would benefit most, including supply constraints in the vaccine doses themselves, vials, syringes and other material, administration constraints and demand constraints stemming from vaccinating those in high-priority groups who could be reluctant to receive a vaccine.

While a single-dose regimen of currently available vaccines may help prevent supply constraints, he wrote, it may lead to greater constraints on demand and administration of the vaccine.

“Offering reluctant populations a less effective regimen of a vaccine, or failing to offer its second dose on schedule, may cause confusion, create a multitiered system of vaccine access, and exacerbate historical concerns that certain groups are more likely to receive substandard care,” Bollyky wrote.

Although funding was recently approved by Congress to help local and state health care systems, he added, it may take weeks to be distribute, which will make administration of the vaccine, rather than the limited number of doses, a greater challenge to vaccine distribution. For instance, he noted that as of Dec. 30, only 2.6 million of 12.4 million distributed doses had been administered to patients in the U.S.

In their statement supporting the FDA’s position on changes to authorized use for the Pfizer and Moderna vaccines, the Infectious Disease Society of America noted that federal leadership needs to be strengthened in order to ensure that funds, including these recently approved funds, reach state and local health department immediately.

“This is necessary to support successful vaccine administration strategies, including expanding staffing for planning and implementation, and working with healthcare providers, healthcare systems and workplaces to operate high-volume sites and ensure timely access to vaccines by eligible populations,” the organization stated.

Bollyky noted that while strategies to stretch vaccine supplies may be useful, they would be more helpful if there are greater limitations in vaccine supplies.

“For now, the priority should be to grow the evidence base by pursuing clinical testing and observational studies to determine whether a single dose or a delayed second dose of the current vaccines will generate immunity similar to that of the FDA-authorized 2-dose regimen,” he wrote. “Supported by strong public health systems, rapid vaccine production and equitable vaccine distribution within the United States and around the world, vaccination strategies driven by data can bring an end to COVID-19.”

CNN reported that President-elect Joseph R. Biden intends to release all available doses of COVID-19 vaccine when he enters office, breaking with the Trump administration’s strategy of reserving stockpiles so that people receive both doses.

References:

• Barnabas RV, et al. Ann Intern Med. 2021;doi:10.7326/M20-8060.
• Bollyky TJ. Ann Intern Med. 2021;doi:10.7326/M20-8280.
• FDA. FDA Statement on Following the Authorized Dosing Schedules for COVID-19 Vaccines. https://www.fda.gov/news-events/press-announcements/fda-statement-following-authorized-dosing-schedules-covid-19-vaccines. Accessed January 5, 2021.
• IDSA. Address COVID-19 Vaccine Access Challenges with Leadership, Funding, Collaboration and Science. https://www.idsociety.org/news--publications-new/articles/2021/address-covid-19-vaccine-access-challenges-with-leadership-funding-collaboration-and-science/. Accessed January 5, 2021.
• Paltiel AD, et al. Ann Intern Med. 2021;doi:10.7326/M20-7866.
• Tuite AR, et al. Ann Intern Med. 2021;doi:10.7326/M20-8137.

Editor’s note: This story was updated with new reporting by CNN.