Can limiting the priming dose of a SARS-CoV-2 vaccine improve immunity?

Several vaccines have been developed, approved and rolled out to prevent coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, some concern is mounting that a sufficient number of vaccine doses may not be available to promptly promote global herd immunity. This predicament has led researchers to explore the possibility of administering partial vaccine doses to boost coverage.

But this, in turn, raises the question of how vaccine fractionation affects vaccine-elicited immunity. In a vaccine fractionation (also known as dose-sparing), a smaller amount of antigen would be used per dose to increase the number of persons who can be vaccinated with a given quantity of vaccine.

In a recently released paper on the bioRxiv* server, researchers from Northwestern University and the University of Rochester in the U.S. addressed this question in their study. The researchers also explored whether the vaccines administered across the world could confer sterilizing immunity while preventing severe disease and death.

A rationale for fractionating SARS-CoV-2 vaccines is that it may result in wider herd immunity even if vaccine efficacy is only partial and that this could have a more striking effect in blocking transmission at the population level.”

Using an adenovirus-based vaccine encoding SARS-CoV-2 spike protein (Ad5-SARS-2 spike), the researchers studied how the priming dose of a SARS-CoV-2 vaccine affects long-term immunity in mice to SARS-CoV-2. This vaccine is similar to that used in the CanSino and Sputnik V vaccines.

They found that low dose (LD) prime induced lower immune responses relative to the standard dose (SD) prime. However, the researchers reported that the LD prime elicited immune responses that are qualitatively superior. And upon boosting, the LD primed mice exhibited significantly more potent immune responses.

Particularly, the researchers found that limiting the priming dose of a SARS-CoV-2 vaccine may confer an unexpected qualitative benefit to T cell responses and antibody responses. They showed that an LD prime favors Tcm differentiation, characterized by high expression of CD127, the IL-7 receptor alpha chain, which allows the T cell to survive long-term.

Also, the researchers observed that the LD/SD regimen induced superior antibody responses compared to the SD/SD regimen. Thus, a “gentle” antigen prime also generates memory B cell responses with significantly superior anamnestic capacity.

Because the effect of an LD prime is strikingly more on the antibody responses than on the T cell responses, the researchers added that their future studies will be aimed at understanding how the LD prime affects memory B cell differentiation.

Based on the data from this study, the researchers argue that limiting the priming dose of a SARS-CoV-2 vaccine may confer unexpected benefits. A single shot of LD/SD provided sterilizing protection. The protective advantage may also be long-term, where in most cases, the vaccine-elicited responses may wane.

The researchers also highlighted that the LD/SD regimen may also be useful to improve vaccine efficacy in individuals who develop suboptimal immune responses to vaccines, and who may benefit from having a higher level of immune responses. With the imminent threat from SARS-CoV-2 variants and re-emergence of SARS-CoV-1, the researchers also showed that the LD/SD regimen resulted in improved cross-reactive antibody responses compared to SD/SD.

While the researchers showed that fractionating the priming dose of an adenovirus-based SARS-CoV-2 vaccine confers an unexpected immunological benefit, the minimum level of immune responses required to protect against severe COVID-19 is yet unclear.

They also noted that the low levels of immune responses protect individuals from the COVID-19, explaining the extraordinary success of multiple experimental SARS-CoV-2 vaccines in the last year.

Vaccine fractionation is an effective strategy to extend vaccine supplies and thwart the pandemic causing infection. Based on the results from this study, optimization of current vaccine regimes may warrant a re-evaluation. These findings may be useful for improving vaccine availability and for rational vaccine design, the researchers conclude.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Ramya Dwivedi

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.


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