Can protein vaccines for COVID-19 win over the vaccine-hesitant?

1. Introduction

The emergence of severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, as a novel human pathogen in 2019 and the global COVID-19 pandemic that ensued prompted a race to develop and disseminate a vaccine against the new coronavirus. Building off decades of prior research, the scientific community put forth numerous candidate vaccines, and late-phase clinical trials began as early as the Spring of 2020. Russia authorized its first vaccine against SARS-CoV-2 in August 2020, and the U.K., the U.S., and China followed with vaccines authorized in December 2020 [1]. Realizing the importance of swift uptake of these vaccines, the trials were accompanied by public awareness campaigns of an unprecedented scope.

During the initial wave of the pandemic, public opinion polls found high rates of willingness to receive a COVID-19 vaccine once one became available [2,3]. In Western Europe and North America, the first vaccines to gain authorization used platforms that were unfamiliar to the public – namely, viral-vectored and mRNA vaccines [1]. While clinical trials of inactivated and protein subunit vaccines were still underway, the mRNA vaccines developed by Pfizer-BioNTech and Moderna and the viral-vectored vaccines developed by Oxford-AstraZeneca and Janssen/Johnson & Johnson were rolled out en masse [1]. These vaccines were embraced by large portions of the population but met with reluctance and skepticism by others. It was hoped that a protein subunit vaccine would provide an option that would be both more familiar to the general public and easier to distribute to parts of the world with limited capacity to handle mRNA vaccines.

As of 30 November 2022, 15 protein subunit vaccines have been authorized for use around the world, but the Nuvaxovid (also known as NVX-CoV2373) vaccine developed by Novavax is the only protein subunit vaccine that has received WHO Emergency Use Listing and authorization and/or licensure as a primary series in the U.S., U.K., E.U., Canada, and Australia [4].

2. Vaccine hesitancy

The factors associated with refusal, reluctance, and acceptance of COVID-19 vaccines have been topics of great interest to those seeking to maximize COVID-19 vaccine uptake. Since COVID-19 vaccines became available, public opinion polls, population surveys, and qualitative studies have evaluated motivations behind the decision to receive any COVID-19 vaccine or not, but few have explored preferences for protein vaccines.

3. Reasons for wanting a protein vaccine

Reluctance around mRNA and viral-vectored COVID-19 vaccines has often been attributed to the perceived novelty of the vaccines. Although the mRNA and viral-vector technologies had been under development for decades prior to the emergence of SARS-CoV-2, no vaccine authorized for general use in high-income countries had ever used either platform. Misinformation about how these platforms worked, including the ability to alter the recipient’s DNA or affect fertility, fanned concerns about side effects, and disinformation about microchips in the vaccines capitalized upon conspiratorial beliefs and mistrust in authorities [5–7].

Religious concerns about the use of embryonic stem cells in the vaccine development and production processes have also been cited as reasons to avoid mRNA and viral-vectored vaccines [8]. Most major organized religions have encouraged COVID-19 vaccination without regard to the platform, but there remain groups who voice an ethical preference for Novavax’s protein-based COVID-19 vaccine [8].

Notably, there is also a small portion of the population that experienced severe, anaphylactic reactions to components of an mRNA vaccine who were advised by their healthcare providers that they should wait for a protein-based vaccine [9].

A more traditional platform, it was argued, could alleviate some of the concerns about potential long-term side effects and contents of COVID-19 vaccines. Together, these seemed to be reasons for optimism that a protein submit vaccine might convince those that remained unvaccinated after approval of first COVID-19 vaccines.

4. Protein vaccine intentions and uptake

A June 2022 Morning Consult survey of 6630 U.S. adults found that 11% of unvaccinated respondents would receive a ‘traditional protein-based COVID-19 vaccine’ if it were authorized while 57% were not planning to receive one and 20% were not sure they would get one. In that survey, 28% of unvaccinated respondents thought protein-based vaccines were safe, while 27% thought that they were unsafe; by contrast, 39% of unvaccinated respondents thought that mRNA vaccines were unsafe, while 17% thought they were safe [10].

Nuvaxovid was authorized for use in U.S. adults 18 years and older on 13 July 2022 and in U.S. teens 12–17 years of age on 19 August 2022 [1]. As of 30 November 2022, 970,900 doses of the Novavax vaccine had been delivered, yet as few as 61,387 total doses had been administered, and roughly 20% of the U.S. adult population had yet to complete a primary vaccination series [11].

5. Reasons for COVID-19 vaccine refusal

The same survey noted that concerns similar to those about mRNA and viral-vector vaccines were major reasons for planned refusal of protein-based vaccines. When asked about reasons for not wanting a protein-based vaccine, 72% of respondents classified concerns about side effects as a ‘major reason’; 66% were worried the vaccine moved through clinical trials too fast, 51% didn’t think the vaccine would be effective, 49% did not trust the manufacturer, 31% thought the risk of getting COVID-19 is small, and 25% were against vaccines more generally [10].

Risk-benefit calculations balance concerns about the safety of vaccination against beliefs about the risks of disease. For those who perceive themselves susceptible to COVID-19, a vaccine option that they believe to be safe and effective might convince them to receive a COVID-19 vaccine. On the other hand, addressing concerns about vaccine safety is unlikely to tip the scales in favor of vaccination for those who perceive themselves to be at low risk of morbidity or mortality due to COVID-19.

Mistrust as a component of vaccine refusal extends beyond concerns about the vaccine products themselves. Mistrust in government is predictive of COVID-19 vaccine refusal [12,13]. Similarly, mistrust in healthcare organizations is associated with decreasing intentions to receive a COVID-19 vaccine [14]. By contrast, trust in one’s healthcare provider has been found to be predictive of COVID-19 vaccine acceptance [12,15].

6. Conclusion

In the U.S., the approval of a protein vaccine against COVID-19 has not led to significant uptake among those not previously vaccinated. There may still be opportunities to convince those who are reluctant about COVID-19 vaccination to receive a vaccine, but a protein vaccine is not likely to win over those who have refused vaccination. Those individuals will likely remain unconvinced until issues of trust are addressed on a much broader scale.

Declaration of interest

E Hammershaimb and T Milagritos are investigators for studies of COVID-19 vaccines developed by Novavax and Moderna for which their institution receives funding through the NIH but do not have a direct financial relationship with either company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.