Next-generation COVID-19 vaccines – looking beyond spike protein and SARS-CoV-1 variants

The response to COVID-19 – a success story in vaccine development

The accelerated development of vaccines against COVID-19 and their deployment in mass vaccination programmes has been a major public health achievement. The landscape of vaccine development has undergone rapid change in the global response to the pandemic, with the utilization of novel platforms to create new vaccines at an unprecedented speed. Despite the success of current vaccines in mitigating the threat of severe disease from SARS-CoV-2 infection, there are some ongoing challenges, and the optimization of COVID-19 vaccines is an area of continuing research.

Limitations of current vaccines against COVID-19

Most COVID-19 vaccines in use and in development are designed to elicit immune responses mediated by neutralizing antibodies against the SARS-CoV-2 spike protein. The key role of the spike protein in mediating viral entry into lung cells (through binding to the angiotensin-converting enzyme 2 [ACE2] receptor and subsequent virus-host membrane fusion) underpins its selection as the main target protein in COVID-19 vaccines. Several of the COVID-19 vaccines currently authorized for use work by instructing our own cells to make copies of the virus spike protein, which are recognized as being foreign by our immune systems. This triggers the production of antibodies against the virus that can prevent it from infecting host cells upon a subsequent infection.
People who are fully vaccinated against COVID-19 are highly protected against severe infection, hospitalization and death. However, breakthrough cases in vaccinated individuals have been reported and may account for the high numbers of infections recently recorded in Israel, a country that was successful in rapid roll out of COVID-19 vaccination and has achieved high coverage levels.1 These trends may reflect a possible waning in vaccine-induced immunity over time, which may call for the requirement for booster vaccinations. It is also possible that the apparent decline in vaccine effectiveness is due to the circulation of SARS-CoV-2 variants that, as a result of ongoing viral evolution, have acquired mutations in the spike protein that allow for the evasion of vaccine-induced immunity.

What’s next for COVID-19 vaccine development?

Given the need to control current and emerging variants of concern that can evade the immune response to available vaccines and undermine their effectiveness, efforts are in progress to develop second-generation vaccines to protect against SARS-CoV-2 variants. As well as improving the breadth of recognition of different variants of SARS-CoV-2, there may also be a rationale for developing next-generation COVID-19 vaccines that are broadly protective against related coronaviruses. SARS-CoV-2 is not the first coronavirus outbreak to impact humans, with outbreaks of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) also having occurred in the last two decades. The development of a ‘pan-coronavirus’ vaccine would be highly desirable to prevent or reduce the risk of future pandemics caused by related coronaviruses with potential to cause severe human diseases.

There is growing evidence that immunity against SARS-CoV-2 through current vaccines is waning.2,3 While there has been a general acceptance that it is imperative for vaccines to elicit neutralizing antibodies responses, antibody levels diminish over time and other immunologic protective mechanisms are likely to be important to induce a longer-lasting immune response more comparable with that elicited by natural infection, including T cell immunity. From experience with other coronavirus infections, T cells responses are thought to offer far more durable protection than antibody responses.4 As expected for a viral infection, CD4+ and CD8+ T cells are important mediators in the host response to SARS-CoV-2 infection, by supporting B cell function and antibody responses and by killing infected cells, respectively.

CD8+ T cells (cytotoxic T lymphocytes [CTL]) can target sequences of viral proteins that are internal to the virus (unlike antibodies that bind proteins on the surface of the virus), some of which are genetically very stable. This raises the possibility of designing vaccines against targets that are less prone to antigenic or genetic drift than spike proteins, and incorporating targets from multiple proteins into one vaccine. There may be other reasons to look beyond spike proteins in the design of next-generation vaccines when we consider insights gained from animal studies on the impact of spike protein on cellular function. Experiments using a spike protein-carrying pseudovirus show that coronavirus spike proteins can induce biological abnormalities in ACE2 receptor-expressing cell types (including blood vessel cells) and potentially cause adverse pathological events.5 Such findings, coupled with the detection of spike protein circulating in the blood of mRNA vaccine recipients,6 have raised some uncertainties on the targeting of spike protein in vaccine design. Whilst it is unknown whether the spike proteins generated by COVID-19 vaccines behave in the same manner as the wild-type spike proteins of SARS-CoV-2 and there is no firm evidence that vaccine-introduced spike proteins are harmful to humans, the findings have raised questions about the safety of spike protein-generating vaccines.

T cell priming offers a novel approach to coronavirus vaccine design

With the potential to deliver fast, broad, and long-lasting immunity, CD8+ T cell priming is a vaccination strategy that lends itself to the design of next-generation COVID-19 vaccines. Priming of naïve T cells by vaccination that are boosted to a memory phenotype upon later infection is expected to facilitate an immediate CD8+ T cell response; this is predicted to contain disease and mimic the natural course of the immune response, leading to development of long-term immunity. Furthermore, the inclusion of T cell epitopes from within conserved regions of the viral genome in such vaccines may reduce the impact of viral mutations on the vaccine-induced immune response and allow for potential protection against new variants and related viruses that share the same conserved epitopes.

T cell-priming is an approach being pursued at Emergex Vaccines for the development of vaccines against several RNA virus infections. A vaccine with the potential to offer broad and long-lasting dual protection against SARS-CoV-1 and SARS-CoV-2, current and future mutations and different variants of concern is due to enter Phase 1 trials. The candidate vaccine targets conserved epitopes from both spike and nucleocapsid parts of the virus. In challenge experiments with SARS-CoV-1, mice which received the candidate vaccine were protected from lung pathology, demonstrating strain cross-reactivity.

Find out more about the science behind T cell priming vaccines and the vaccines being developed using this approach at Emergex Vaccines by visiting


    • Wadman M. Israel’s grim warning: Delta can overwhelm shots. Science 2021;373:838 –839
    • Levin EG et al. Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months. N Engl J Med 2021 Oct 6. doi: 10.1056/NEJMoa2114583
    • Chemaitelly H et al. Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar. N Engl J Med 2021 Oct 6. doi: 10.1056/NEJMoa2114114
    • Hellerstein M. What are the roles of antibodies versus a durable, high quality T-cell response in protective immunity against SARS-CoV-2? Vaccine X 2020;6:100076
    • Lei Y et al. SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2. Circ Res 2021;128:1323–1326
    • Ogata AF et al. Circulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Antigen Detected in the Plasma of mRNA-1273 Vaccine Recipients. Clin Infect Dis 2021 May 20;ciab465. doi: 10.1093/cid/ciab465