by Dominik Sarma

The Status Quo

The current COVID 19 pandemic caused by SARS-CoV-2 is claiming many lives, endangering global peace, international cohesion, and causing enormous economic damage. We can only counter this threat in the long term if the virus is completely suppressed. This can be achieved if so-called herd immunity is achieved for all people worldwide. This means that enough people are immune (approx. 40-80 %) so that the virus can no longer find a host.[1,2] 

There are two conceivable ways of doing this: infestation with the virus or vaccination of a large proportion of society (40-80%). An infestation cannot be the goal, as this would endanger millions of lives. The case fatality rate (CFR) of COVID-19 is calculated to be between 0.25-3.0% of the total population, which means that the estimated number of people who could theoretically die from COVID-19 to achieve herd immunity is difficult to accept for a society.[3]

Additionally, it remains to be demonstrated that COVID-19 survivors are immune (i.e. protected) against reinfection in the long term. Therefore, an efficient vaccine that is easily produced and delivered to large proportions of society remains the goal of a worldwide fight against the SARS-CoV-2 virus.

There are currently 33 vaccines in clinical and 143 in preclinical trials (Figure 1).[4] The largest share among all candidates holds vaccines based on protein subunits (N = 53, 30%).

Figure 1: Percentage distribution by type of vaccine against the SARS-CoV-2 

Usually, the development of a vaccine takes several years. We do not have that time. Therefore, a strong focus lies on vaccines that can be produced quickly on a large scale and whose safety profile allows the quick initiation of clinical trials in humans. These include, for example, (chemical) synthetic approaches such as RNA/DNA- or peptide-based vaccines. While the former contribute 42 (24%) candidates, peptides remain a smaller party of 12 applicants (7%). 

Let's have a look at the most advanced nominees. The large majority target the spike protein and mainly induce humoral immunity by B-cell activated antibody protection. However, some persistent uncertainties come along with this approach:

- It's yet uncertain if the antibodies can efficiently prevent infection with SARS-CoV-2 in humans.

- Recent studies show a fast decaying antibody titer after infection. [5]

- The constant mutations of the virus can lead to antigenic drifts that might make the antibody (and the vaccine) ineffective over time. [6]

- There remains some apprehension about antibody disease enhancement (ADE).[7]

Thus, there is a need to explore complementary vaccination strategies to promote virus-specific, long-term, and save immunity. Synthetic peptides inducing long-lasting T-cell (memory) responses can be a way out. 

Precision tools to defeat the virus

Recent study results provide evidence that cellular immunity can effectively combat the SARS-CoV-2 virus.[8,9] This form of immunization is controlled by T-cells that can be stimulated by peptide fragments (epitopes) of the virus that bind to major histocompatibility complex-I/II to orchestrate the killing of infected cells.[10]

In-silico or bio-screening supported discovery programs allow for the identification of potential hits, followed by their validation through immune response assays with blood samples from convalescent COVID-19 patients before entering safety studies with animals and progressing into clinical trials. The precise identification of immunogenic, small conserved fragments of the whole viral proteome offers vital advantages such as

(a) high safety profile with minimal risk for ADE,

(b) account for minor citizen genotypes, and

(c) escape from antigenic-drift.[11]

Yet, peptide epitopes alone cannot induce active T-cell immunization because our immune system does not recognize native sequences as a foreign body. It is, therefore, necessary to use a signaling substance - an adjuvant - which stimulates an inflammatory process. These adjuvants can be added and packaged in molecular nano or micro vehicles or covalently coupled to the epitope.

The preclinical road to a peptide-based vaccine against the Sars-CoV-2 is an interdisciplinary journey from epitope discovery, to their synthesis and validation, and also the vaccine design including an adjuvant and formulation strategy. Within each of these aspects, the safety profile and stability of the final product must comply with GMP to ensure a global supply, and in consequence, the urgently needed herd immunization. 

What's in for peptides 

We have looked thoroughly through the 12 peptide-vaccine candidates (Table 1). The frontrunner, and yet the only candidate in clinical trials, was developed at the Russian State Research Center of Virology and Biotechnology "Vector". More projects are expected to enter first-in-human trials during this fall. 

For all candidates, we added information about the discovery platform as well as the (potential) formulation strategy when they were available since both are vital for the future application of the vaccine. Moreover, we added some experimental approaches that reflect well the diversity and global power peptide companies and research groups can bring together for this decisive duel #peptidesVSvirus. 

Table 1. Tabular overview of peptide-based vaccine candidates against SARS-CoV-2.

[1] Britton, T. et al. A mathematical model reveals the influence of population heterogeneity on herd immunity to SARS-CoV-2, Science 2020, 369, 846 - 849 (link)

[2] Kwok K. O. et al. Herd immunity - estimating the level required to halt the COVID-19 epidemics in affected countries. Journal of Infection 2020, 80, e32 - e33 (link)

[3] Wilson, N. et al. Case-Fatality Risk Estimates for COVID-19 Calculated by Using a Lag Time for Fatality, Emerging infectious diseases 2020, 26, 1339-1441 (link)

[4] WHO, Draft landscape of COVID-19 candidate vaccines, as of 30.08.2020 (link)

[5] Long, Q.-C. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections, Nature Medicine 2020, (link)

[6] Giurgea, L.T. Universal coronavirus vaccines: the time to start is now. npj Vaccines 2020 (link)

[7] Garber K. Coronavirus vaccine developers wary of errant antibodies. Nature News from 05.06.2020 (link)

[8] Grifoni et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 2020, 181, 1489–1501 (link)

[9] Braun, J. et al. Presence of SARS-CoV-2 reactive T cells in COVID-19 patients and healthy donors. medRxiv 2020.04.17.20061440 2020 (link)

[10] Krogsgaard, M. How T cells 'see' antigen, Nature Immunology 2005, 6, 239 - 245

[11] Malone, B. et al. Artificial intelligence predicts the immunogenic landscape of SARS-CoV-2: toward universal blueprints for vaccine designs. medRxiv 2020.04.21.052084 2020 (link)