During the initial stages of the coronavirus disease 2019 (COVID-19) pandemic, the International Monetary Fund estimated that a cost of $12 trillion in short-run GDP losses alone might take place over two years. Subsequent estimates that include health costs and long-run impacts would be much larger. Based on these estimates, it can be inferred that the cost of accelerating mass vaccination by even a month would be $500 billion.
The high value of accelerating vaccination suggested that the decision to invest in multiple vaccine candidates along with parallel research and development had more social value rather than sequence investments. A rough estimate suggested that the US Operation Warp Speed (OWS) would require to pay for itself if it advanced vaccination in the United States by even a day.
Although OWS generated sufficient vaccines for the United States, several countries still face a supply shortage. Pursuing multiple options similar to at the beginning of the pandemic can help improve vaccine delivery systems, use existing supply more efficiently, invest in expanding supply, and as insurance against a range of scenarios such as the emergence of new variants or shocks to the supply chain.
Administration of lower doses of vaccines is one such option. Fractional dosing has been implemented in the past for multiple diseases on advice from the World Health Organization (WHO). Several studies on COVID-19 suggested that half or even quarter doses of some vaccines could have the same efficacy as the original doses of the vaccine. Also, they might have fewer side effects. Lower doses are already being implemented as booster doses and in children.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concerns (VOCs) indicated that outbreaks could occur in populations that have been vaccinated with a highly effective vaccine. However, less effective vaccines are observed to be effective in preventing hospitalization and deaths, even for VOCs. Studies also suggested that in areas with constrained vaccine supply or where VOCs dominate, fractional dosing could protect more of the population from death and severe disease.
Research on optimal dosing for vaccines is important for three main reasons, many countries still face a shortage of vaccines, lower doses of some vaccines may be more effective than the standard doses, and lower doses may be superior if they provide comparable effectiveness at lower side effects.
A new study published in PNAS assessed the benefits of using fractional doses for curbing the current COVID-19 pandemic.
Effectiveness of lower doses
Fractional doses of some vaccines were reported to produce immune responses similar to large doses and greater than those produced by the standard doses. The efficacy of the lower doses was found to be similar to the standard doses and falls within the 90-95% range for symptomatic disease.
The decrease in protection against deaths and severe diseases was smaller in the case of fractional doses compared to the standard doses in response to VOCs. Furthermore, since large unvaccinated populations have acquired immunity against SARS-CoV-2 due to natural infections, they might need only one vaccine dose for protection against reinfection. Young adults and children also require lower doses since their immune responses are stronger.
Booster doses have been considered by many countries to improve public health outcomes. Administration of lower doses could help to decrease the burden on the global vaccine supply due to boosters.
Impact of lower dosing on public health
During a shortage of vaccines, switching to lower doses and vaccinating more people can help to improve public health outcomes. Even if the efficacy of the vaccines is reduced, it is better than leaving people entirely unprotected.
The epidemiological model used in the current study suggested that even in scenarios with emerging new VOCs, as well as if the efficacy of lower doses is quite low, the fractional doses would help save lives.
Risks associated with using lower doses
Several risk factors were found to be associated with lower doses. First, the current study does not include the rate of immunity loss that might be impacted due to modification of dose size. Second, it may lead to the emergence of more harmful variants due to selection pressure. Third, vaccination programs, including lower doses, are considered inequitable. Finally, switching to fractional doses can lead to vaccine hesitancy.
Testing of lower doses
Fractional dosing for COVID-19 vaccines has not been recommended by any regulatory agency or immunization advisory group. The WHO Strategic Advisory Group of Experts has encouraged more research on fractional dosing.
Few studies on fractional dosing are being carried out, such as an observational study with half doses of ChAdOx1 nCoV-19 in Brazil and two randomized immunogenicity trials comparing low doses for mRNA-1273 and BNT162b2 vaccines.
Data on the immunogenicity of fractional doses may help policymakers recommend their use in national vaccination campaigns, especially for lower-risk groups and young adults. Policymakers and researchers of lower- and middle-income countries showed interest in testing fractional studies and changing the current recommendations. However, the approach and decisions were based on unique factors to an individual country.
Existence of gaps between commercial incentives and the social value of research on optimal dosing
Although some vaccine manufacturers have been reported to carry out trials on functional dosing for children and boosters, private companies are not inclined to research fractional dosing. There can be three reasons for this, companies would lose revenue if more doses were drawn from each vial without changing the vial price, manufacturing vials with specific doses can lead to substantial sunk costs, seeking approval for new doses is both time-consuming and costly, and firms might face a reputational risk if something goes wrong with the lower dose.
Government investments in testing for fractional doses can have high benefits as well as high payoffs. Global institutions are suggested to invest in and coordinate studies on fractional dosing since it can impact decision-making in several countries.
Importance of dose optimization late in the pandemic
Research on fractional dosing is considered important even late in the pandemic. In case of possible shocks that can delay vaccine supply, fractional dosing can be beneficial. Furthermore, several studies estimated that vaccine shortages would continue until March 2022. During such scenarios, fractional dosing can be of importance.
Also, the eventual distribution of booster doses in middle- and low-income countries may further decrease the available supply for primary series vaccination elsewhere. Additionally, fractional dosing has other benefits, such as lower side effects along with comparable efficacy with standard doses. It can increase the supply of the most effective vaccines, thereby improving vaccine equity and public health outcomes.
The study suggested that fractional testing has large potential benefits and switching to fractional dosing can help to accelerate vaccination and save lives in several countries. Fractional doses might be more effective than the current standard doses in many countries and have lower side effects.
However, fractional doses are associated with few risks, and some logistical questions remain unanswered. Further research needs to be carried out on fractional doses for the determination of optimal doses for each country which the policyholders can thereafter implement for the improvement of public health outcomes.