Since late 2019, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the globe, and the resulting coronavirus disease 2019 (COVID-19) pandemic has had unprecedented impact on healthcare systems, economics, and social interactions. At similarly unprecedented speed, the development, clinical investigation, and regulatory assessment of COVID19 vaccines have been pursued1, resulting in emergency use authorization (EUA) of several vaccines just about one year after the virus had initially been described. The first two formulations licensed in Western countries – Comirnaty (BioNTech-Pfizer) and Spikevax (Moderna) – employed an mRNA vaccine technology, while shortly thereafter, two vaccines based on recombinant adenoviral vectors – Vaxzevria (AstraZeneca) and Janssen COVID-19 Vaccine (Janssen) – received regulatory approvals in the European Union (EU) or the United States (US); all of these vaccines were characterized by high efficacy across gender, age groups and ethnicities2–5.
Another large group of COVID-19 vaccine candidates employs the biotechnological production of immunogenic viral proteins or protein subunits, in case of SARS-CoV-2 the spike (S) protein or its receptor-binding domain1. One of these candidates is NVX-CoV2373 (TAK-019; Novavax), a recombinant nanoparticle vaccine for which safety and immunogenicity6 and subsequently high efficacy7 have been demonstrated. Compared to mRNA vaccines, long-term storage above freezing is a beneficial characteristic that is especially important for the supply of low- and middle-income countries. Correspondingly, as the first protein-based vaccine, NVX-CoV2373 has recently been granted EUA in Indonesia8 and the Philippines9, as well as a conditional marketing authorization in the EU10.
Large vaccination campaigns have meanwhile substantiated the effectiveness of the aforementioned mRNA- and vector-based vaccines, especially with respect to severe COVID-19 and thus COVID-19-related death. With respect to further vaccine candidates currently in the pipeline, there is a demand for estimating such performance indicators upfront, as the global reduction in case numbers (due to the already licensed vaccines) and ethical considerations (avoiding placebo groups when vaccines are already standard care) argue against large phase 3 efficacy studies11. Not unexpectedly, the levels of SARS-CoV-2 neutralizing antibodies (nAbs) have recently been identified as an informative correlate of protection12,13, i.e., measuring SARS-CoV-2 nAbs in serum samples of vaccinees enables to predict the risk of developing COVID-19. However, while the clinical evaluation of vaccine candidates frequently includes a nAb readout, the heterogenous design of the underlying virus neutralization assays limits the quantitative comparison of the primary result (the neutralization titer) across distinct studies. These technical hurdles can be alleviated by the incorporation of an international standard, which has recently been made available to study SARS-CoV-2 antibody-containing samples14, but not yet used for vaccine evaluations and comparisons.
In the present study, we made use of this first international SARS-CoV-2 antibody standard and directly compared the nAb levels in response to a protein-, an mRNA- and a vector-based vaccine. All study subjects were confirmed to have been initially seronegative (no detectable SARS-CoV-2 neutralization for samples obtained at the day of first vaccination). Samples from individuals vaccinated either with NVX-CoV2373 (n = 30), Comirnaty (n = 35) or Vaxzevria (n = 12) were collected 15 to 32 days after complete immunization (2 doses of the respective vaccine; Table 1). Average post-vaccination anti-SARS-CoV-2 potency was 548 IU/ml, 557 IU/ml, and 202 IU/ml for recipients of NVX-CoV2373, Comirnaty, and Vaxzevria, respectively (Figure 1). ANOVA (P = 0.004) and post-hoc pairwise comparisons confirmed that mean SARS-CoV-2 nAb levels were equivalent for NVX-CoV2373 and Comirnaty groups (adjusted P value: 0.998) and significantly lower for the Vaxzevria group (adjusted P values: NVX-CoV2373 vs. Vaxzevria: 0.007; Comirnaty vs. Vaxzevria: 0.005).
Previously, the explanatory power of SARS-CoV-2 nAbs with respect to vaccine efficacy has been investigated by an indirect approach, i.e., via normalization of neutralization titers to cohorts of convalescent (post-COVID-19) individuals analyzed in parallel12,13. However, such cohorts are subject to considerable variation (e.g., due to different parameters that define convalescence, due to diverging fractions of individuals that had suffered from severe versus mild disease, or sample size), as is the sequence of mathematical operations for normalization. Thus, while Khoury et al. found the average SARS-CoV-2 nAb levels induced by Vaxzevria to be lower than average post-COVID-19 levels12, Earle et al. found slightly higher mean anti-SARS-CoV-2 potency of the vaccine13. The latter result is similar to our own data, as the mean vaccine-induced SARS-CoV-2 nAb level of 202 IU/ml (Table 1) is above the mean (140 IU/ml) of a post-COVID-19 group analyzed in one of our earlier studies15. The accuracy of the earlier used comparison to convalescent plasma for normalization must therefore be considered as limited.
In contrast, the results of the present study are derived from the same assay and provide a first direct comparison of the SARS-CoV-2 nAb response between three COVID-19 vaccines based on different immunogenic principles. Comparable anti-SARS-CoV-2 potency in sera of NVX-CoV2373 and Comirnaty recipients and the slightly lower levels in response to Vaxzevria are in line with previously published levels of vaccine efficacy2,4,7, directionally confirm the previous, more indirect approaches12,13 and lend further support to the notion that neutralizing antibody responses represent a suitable correlate of protection. While distinct ethnicities might be a confounding factor of the present study, it should be noted that diverging COVID-19 vaccine efficacy between Asian and White vaccine recipients has not been reported2,4. Most importantly, the calibration of results against the first international SARS-CoV-2 antibody standard14 allows for an objective comparison beyond the present study population.