The relationship between neutralization levels and observed efficacy against asymptomatic and symptomatic infection of ten COVID-19 vaccines

In a recent study published on the medRxiv* server, researchers determined whether levels of neutralizing antibodies (NAb) were predictive of the efficacy of fractional vaccine doses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study: Predictive efficacy of vaccine dose fractionation using neutralizing antibody levels. Image credit:


During the 2016 yellow fever outbreak, Angola and the Democratic Republic of the Congo (DRC) used fractional doses of the 17DD yellow fever vaccine to accelerate the vaccine rollout and successfully combat yellow fever with 1/5 of the standard vaccine dose. Similarly, during the 2022 outbreaks of the monkeypox virus in the United States, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the reduced volume (one-fifth) JYNNEOS vaccine to reduce the incidence of monkeypox infections reduced by intradermal injection.

Vaccine dose fractionation could be an effective strategy to overcome vaccine shortages and their increasing ineffectiveness amid the continued emergence of immunity evading SARS-CoV-2 variants. Most importantly, they can have similar VEs as opposed to the standard doses. Unfortunately, clinical trials primarily test standard vaccine doses rather than fractional doses. However, the immune response in the form of NAb titers is a sufficient correlate of VE from fractional vaccine doses.

About the study

In the current study, researchers first conducted a systematic review of 51 peer-reviewed studies of inside-host models of SARS-CoV-2 in PubMed on March 15, 2022. They extracted relevant information about vaccines (10 strains) and participants (vaccinated or recovering) from the 13 selected studies. They analyzed the relationship between in vitro NAb neutralization levels and the VEs of 10 COVID-19 vaccines against SARS-CoV-2 infection(s). In particular, all reported studies followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

The relevant information included the vaccine name, platform (mRNA or non-mRNA), schedule and standard dose, defined as the dose approved for Phase III studies. Furthermore, they extracted the type and date of the neutralization test used in a study. They also paid attention to the sample size and age of vaccinated participants and convalescents in each included study. In addition, the team used either a random or a fixed effect model to perform a meta-analysis, depending on the heterogeneity between studies.

Because different studies used different assays, the team standardized the NAbs level for each study as the ratio of vaccine-induced NAbs level versus NAbs measured in convalescent sera. They called it the “average neutralization level” and linked it to the 95% confidence intervals (CIs). During the study period after vaccination was completed for each dose, they selected the peak NAb level to model the relationship between NAbs level and vaccine efficacy.

Research findings

The researchers identified 2811 studies through an electronic search on PubMed and excluded 2777 duplicates. They screened the full text of 83 studies, of which only 51 met the inclusion criteria of the current systematic review. Furthermore, they collected 13 records from Pubmed or VE against asymptomatic and symptomatic infection by 11 COVID-19 variants (e.g., Omicron and Delta) and 10 types of vaccines (e.g., BNT162b2 and CoronaVac). The rooted mean square error (RMSE) for the predicted VE for asymptomatic and symptomatic infection was 2.43 and 0.16%, respectively, assessed by the logistic model based on the information from standard dose vaccines.

Compared to recovery levels, VE against asymptomatic (8.8% to 71.8%) and symptomatic (33.6% to 98.6%) infection increased. Similarly, average neutralization levels increased from 0.1 to 10 times the recovery level. Interestingly, the VE of mRNA vaccines, which confer the most robust protection, slowly declined for fractional dosing between 50% and 100% dosing. Protein subunit vaccines also showed a significant upward trend of VEs over dose fractionation. For example, in the dose fractionation study range of 0.03 to 5 doses, protein subunit vaccines showed a VE increase of 5.2% to 59.6% against asymptomatic and 19.4% to 98.4% against symptomatic infection.


The current study results were consistent with studies predicting immune protection against symptomatic COVID-19 infection. The researchers further predicted fractional dose VE against asymptomatic infections.

According to the authors, vaccination with fractionated doses could help to optimize the availability of vaccine doses, especially if vaccine shortages persist worldwide. But even with an ample supply of COVID-19 vaccines, this strategy would still be highly beneficial for susceptible individuals. It could provide them with partial immunity against SARS-CoV-2 reinfection(s) with limited side effects. In addition, fractionated vaccination would help reduce costs and resources required to contain future COVID-19 outbreaks.

*Important announcement

medRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guiding clinical practice/health-related behavior, or established information.

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