Beta-containing COVID-19 booster vaccine found to cross-neutralize variants in non-human primates

Early in 2021, vaccines were rolled out against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), decreasing the number of infections, hospitalizations, and mortality rate.

However, the emergence of new variants of concern (VOCs) in quick succession raised questions about the ability of the vaccines then available to counteract or protect against these variants, underscored by the rising number of breakthrough infections and the strong evidence of a rapid falling off of protective immunity within a few months of the second dose. This also raised interest in administering booster doses to keep protective antibody levels high.

A new paper presents preliminary evidence that a new vaccine candidate, designed to boost immunity in already immunized individuals, and containing the adjuvanted Beta spike variant protein antigen, can induce a potent cross-neutralizing antibody response in non-human primate models that is detectable for up to three months.

The paper is available as a preprint on Research Square*.

Introduction

The SARS-CoV-2 Omicron VOC began several consecutive waves of new infections and breakthrough infections. Booster vaccines were then developed that include antigens specific to the variants in current circulation.

However, the efficacy of this strategy depends on the correctness of multiple postulates. For instance, it needs a timely rollout of vaccines active against currently circulating variants before a new variant arises that can displace the former. Similarly, the booster vaccine doses must elicit a robust response against the specific variant in circulation in a population that has received the primary protocol.

Ideally, several booster doses would be given each year to keep up with the change in currently circulating variants, typically at a gap of 3-4 months, since November 2021, when the Omicron BA.1 variant was first detected. New booster vaccines can unlikely be developed fast enough to keep up with this pace.

It is known that immune imprinting takes place after many immune exposures. This refers to the narrowing of the neutralizing antibody (nAb) repertoire after natural infection or immunization to the cross-reactive one. To circumvent this, a single antigen with high immunogenicity could be selected to alter the immunodominant responses of the original vaccine, but which allows for a range of nAbs directed against several VOCs, including the one in circulation at the time.

The Beta spike variant of SARS-CoV-2 fulfills these criteria and was used in the current booster vaccine candidate.

What did the study show?

Earlier, the scientists demonstrated a D14 spike candidate that was both safe and immunogenic. Following the emergence of the Beta variant in South Africa, they now used this spike variant in the candidate booster candidate. They conducted a non-human primate (NHP) study since earlier studies showed robust cross-reactivity against the VOCs identified so far and even severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) when they had previously been primed with the D14 vaccine.

Following this, two phase 3 clinical trials showed that their Beta-based booster vaccine elicited a broad range of neutralizing antibodies when the recipients received the primary course of a messenger ribonucleic acid (mRNA) vaccine. The potent response also protected against symptoms of coronavirus disease 2019 (COVID-19) following prior natural infection.

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As expected from earlier research, the Beta variant spike-based vaccine produced strong cross-neutralizing antibodies. The durability of this protection was assessed and found to be identifiable even six months afterward. In addition, memory B cells were boosted by vaccines containing either the ancestral D14, Beta variant, or both (bivalent booster, in NHPs who had received mRNA or protein subunit vaccines earlier.

The NHPs showed a protective response detected at six months, against Omicron BA.1 and SARS-CoV-1, in all animals. Animals that had shown a low spike-specific memory B cell response after the primary protocol showed an increase in this aspect of immunity three months after the booster dose.

These B cells “may have a critical role in controlling the viral replication when activated, such as in cases of breakthrough infections… are highly durable and may contribute to protection from disease.”

What are the implications?

While current COVID-19 vaccines provide robust protection against severe disease and death, the nAb titers wane significantly within a few months of the last dose. This was associated with rising rates of breakthrough infections, particularly with the emergence and spread of the Omicron strain.

While bivalent vaccines containing both the ancestral spike and the latest Omicron spike at the time of vaccine development have been recommended in some countries, it appears from available data, albeit scarce, that this is not associated with an adequate rise in protective efficacy compared to the parental vaccines, against all SARS-CoV-2 variants. Moreover, protection against infection by Sarbecoviruses not closely related to the current virus decreased. These results are potentially important and need to be validated and confirmed.

The current study’s authors had earlier shown that the booster vaccine candidate containing Beta spike increased the nAbs against the parental strain by almost two times. This was true of formulations containing the Beta spike alone or in combination with the ancestral spike. In addition, it induced potent cross-neutralizing antibodies against five VOCs, the Alpha, Beta, Gamma, Delta, Omicron, and SARS-CoV-1.

The current study confirms and extends the earlier findings by demonstrating the persistence of these nAbs for up to six months from the booster dose, considering a range of formulations. These titers showed a slight decrease over time, at up to five-fold over 100 days if the priming doses were with mRNA vaccines.

Conversely, with subunit vaccine priming doses, the Beta spike-based booster was associated with a small fall in anti-D614G nAb titers at 100 days, by about four-fold, but not in the other formulations. Independent of the initial priming vaccine platform, the Beta-containing vaccine booster might offer durable and high cross-neutralizing antibody responses to all VOCs and to SARS-CoV-1 for six or more months.

The increased peak nAb titers and a slower rate of decay could mean a higher titer of protective antibodies for a longer period after boosting with Beta spike-based vaccines, with clinical superiority over the currently used booster vaccines, especially as nAb titers stabilize at six months, indicating durable protection compared to the mRNA vaccines in use at present.

The potent and prolonged booster effect up to 6 months against VOCs in NHPs, combined with the encouraging preliminary results from clinical trials presents unique benefits for future booster vaccination campaigns.”

*Important notice

Research Square 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.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.