COVID-19 Vaccine Development - Part 1: Progress and Challenges

The enormous societal impact and global mortality, now over 150,000, that has resulted from the rapid spread of SARS-CoV-2, an enveloped RNA virus, underscores the criticality for accelerated development of vaccines. RNA viruses in general are usually associated with high mutation rates, so allowing evasion of an immune response. Fortunately, SARS-CoV-2 seems to have a moderate rate of mutation, so it should be susceptible to a vaccine, and the race is on to find one! Hope of a successful vaccine is bolstered by reports that immunity to other corona viruses is sustained. There is a report that 17 years later, a SARS survivor still had neutralizing antibodies (Nabs) capable of neutralizing the virus. Results from two studies of antibody levels after infection with SARS-CoV, a similar corona virus, suggest that high levels of IgG may last for up to 1-2 years after infection (Wu et. al. 2007; Guo et. al.2020). However, it has also been described that the level of NAbs post COVID-19 was variable and even undetectable in some patients. Besides, some patients infected with SARS-CoV-2 have been re-hospitalized with COVID-19 with doubts as to whether this was due to re-infection or reactivation of the initial infection. These cases raise questions regarding the quality of post-infection immunity in at least a sub-set of the population (Wu et. al. 2020) although it has also been reported that these could be due to erroneous PCR tests. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30788-1/fulltext  

By mid-April 2020 there were reported to be 79 vaccines in development against COVID-19 (Milken Institute). Five of these were in early clinical trials and more are soon to follow.  Many different concepts and platforms are being explored simultaneously, including live vectored vaccines, protein sub-unit vaccines, mRNA and DNA vaccines, virus-like particles (VLP) and others. Many of these sponsors are being supported by institutions such as CEPI, Gates Foundation and the U.S. Government’s Biomedical Advanced Research and Development Authority (BARDA).  

An important consideration in vaccine design is assessment of the underlying antigenic target and avoidance of vaccine-related disease exacerbation. Most vaccines under development, target the spike or S protein of SARS-CoV-2 that binds to the host ACE2 receptor through which the virus infects host cells. The S protein is comprised of two subunits, designated S1 and S2. The S1 unit contains the receptor binding domain whereas the S2 subunit anchors into the shell of the virus. A membrane fusion sequence near the junction of the subunits, facilitates entry into the host cell following binding to the ACE2 host receptor.  The receptor binding domain is considered a particularly promising target.  It has been found in the case of related corona viruses to elicit not only humoral immunity (production of antibodies) that may result in blockade of viral entry into host cells, but also to induce T-cell immune responses (Ni et. al. 2020). It has been reported that patients with specific HLA type do much better after becoming infected e.g. with malaria highlighting the need to trigger favorable T-cell responses, rather than relying solely on antibody responses, which as discussed above may not always have the desired effect (Lane2020).  

Vaccines developed against the related 2002/2003 SARS-CoV, targeting the S protein, have been studied in animals.  Mostly protective effects have been observed but antibodies to some epitopes have generated antibody-dependent enhancement (ADE) of disease. ADE is a mechanism that facilitates viral entry into host cells and has been reported with several viral infections including Dengue, Ebola, HIV and with other corona viruses (Mazzocco 2020). Unfortunately, no clear pattern emerges as to which region on the S protein might be associated with disease-enhancing antibodies.   The receptor binding domain, the membrane fusion sequence and other sequences seem to be implicated with both protective and disease enhancing antibodies.  Wang et al. 2016 suggested that the risk of ADE may not be associated with the S1 subunit but the full-length spike antigen.  However, it has been reported that a neutralizing monoclonal antibody targeting the receptor-binding domain of the spike protein of the related Middle East respiratory syndrome (MERS) virus can enhance viral entry (Cao et. al. 2020).   A recent study with MERS-CoV and SARS-CoV neutralizing monoclonal reported that antibodies that bind to the receptor binding domain of the respective spike proteins were capable of mediating viral entry into FcR-expressing human cells, thus confirming the possibility of coronavirus-mediated ADE (Wan Y et al. 2020). This may be a gating event for the immune response dysregulation that has been observed with COVID-19.  Certainly, lymphopenia is an early warning for rapid decline that can occur in the second phase of the illness.    

SARS-CoV shares close to 80% homology with SARS -CoV-2 (Yuan et. al. 2020) but extrapolation of findings to SARS -CoV-2 need to be cautious in that there are clearly significant differences in infectivity and mutations that fundamentally change the properties of the spike protein.  Nevertheless, for now SARS-CoV studies provide the best data that exist. There has also been speculation that antibodies generated against corona viruses that cause the common cold which shares 50 -60% homology with CoV-2 S protein may cross react to generate ADEs that accumulate over time so explaining the increasing risk of disease severity with age.  

Another mechanism by which anti-COVID-19 vaccines might give rise to exacerbation of disease is a process known as enhanced respiratory disease exacerbation (ERD), which has been observed to be associated with a formaldehyde-inactivated vaccine that had been developed against respiratory syncytial virus (FI-RSV). Infants vaccinated with the candidate FI-RSV vaccine developed a more severe infection when exposed to natural infection and two babies died. It was found that there were immune complex deposition and complement activation in the small airways and an allergic inflammation, Th2 biased with CD4 T-helper cells production of IL4, IL5 and IL13 associated with pulmonary eosinophilia, mucus production and neutrophilic alveolitis. ERD was caused by an imbalance between high levels of binding antibodies production and weak induction of antibodies with neutralizing and fusion-inhibiting activity and a Th2 pulmonary allergic inflammation (WHO).  A similar response has been observed in animal studies with subunit vaccines to SARS -CoV but reportedly not with RNA and DNA vaccines (Graham 2020). Like for RSV, a potential shift in immune response from the Th1 to Th2 response has been observed in mice that have been primed with a vaccine for SARS. Bolles et. al. 2011, reported in a study in mice that upon re-challenge post-vaccination for SARS, an enhanced immune pathology within the lungs occurred compared to non-vaccinated mice. Previous studies by Deming et. al. 2006 and Yasui et. al. 2008 both showed a similar response in SARS-CoV testing with mice, and point to an exaggerated Th2 response. However, specifically they suggest that the nucleocapsid based vaccinia virus elicited a much stronger immune pathology within the lungs than the S-protein.  

Faced with navigating these issues, WHO has created a consortium of advisors tasked specifically with looking at “vaccine enhancement” to focus specifically on concerns around ADE and this exaggerated immunopathology. They anticipate publishing a report around COVID-19 related findings in the coming months, but a specific timeline is not clear.  

Clearly, the potential for vaccines to enhance rather than protect against infection through the two mechanisms of ADE and ERD highlights the need for studies in animal models. Animal models and early phase clinical studies are discussed in the next blog and will play a key role in assisting rapid navigation to a successful vaccine.  

References

1. Bolles M, Deming D, Long K, Agnihothram S, Whitmore A, Ferris M, Funkhouser W, Gralinski L, Totura A, Heise M, Baric RS. A double-inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. Journal of Virology 2011; 85(23): 12201–12215. doi: 10.1128/JVI.06048-11  
2. Cao, X. COVID-19: immunopathology and its implications for therapy. Nature Reviews Immunology 2020. DOI https://doi.org/10.1038/s41577-020-0308-3 https://www.nature.com/articles/s41577-020-0308-3
3. Deming D, Sheahan T, Heise M, Yount B, Davis N, Sims A, Suthar M, Harkema J, Whitmore A, Pickles R, West A, Donaldson E, Curtis K, Johnston R, Baric R. Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants. PLoS Medicine 2006; 3(12): e525. Erratum in: PLoS Medicine 2007; 4(2): e80. doi: 10.1371/journal.pmed.0030525
4. Graham, Discussion at ADVAC advanced course on  Vaccine development platforms: application to coronavirus (progress and challenges) 2 April 2020. https://www.advac.org/index.php?option=com_content&view=article&id=80:vaccine-development-platforms-application-to-coronavirus-progress-and-challenges&catid=20:webinar-alumni
5. Guo X, Guo Z, Duan C, chen Z, Wang G, Lu Y, et al. Long-Term Persistence of IgG Antibodies in SARS-CoV Infected Healthcare Workers. 2020:2020.02.12.20021386
6. Ni L, Ye F, Chen M-L, Feng Y, Deng Y-Q, Zhao H, Wei P, Ge J, Li X, Sun L, Wang P, Liang P, Guo H, Wang X, Qin C-F, Chen F, Dong C. Characterization of anti-viral immunity in recovered individuals infected by SARS-CoV-2. medRxiv 2020. Doi:https://www.medrxiv.org/content/medrxiv/early/2020/03/20/2020.03.17.20036640.full.pdf
7. Lane R. Sarah Gilbert: carving a path towards a COVID-19 vaccine www.thelancet.com Vol 395, 1247 April 18, 2020
8. Mazzocco G. Safety considerations for COVID-19 vaccines and antibody-based therapies. Ardigen Blog 9 April 2020. https://ardigen.com/safety-considerations-for-covid-19-vaccines-and-antibody-based-therapies/
9. Milken Institute COVID-19 treatment and vaccine tracker. https://milkeninstitute.org/sites/default/files/2020-04/Covid19%20Tracker%20NEW4-8-20-KR%5B1%5D.pdf  
10. Petherick, A. Developing antibody tests for SARS-CoV-2. Lancet World Report Vol 395, (10230), 110-1102 April 4 2020. DOI:https://doi.org/10.1016/S0140-6736(20)30788-1
11. Wang Q, Zhang L, Kuwahara K, Li L, Liu Z, Li T, Zhu H, Liu J, Xu Y, Xie J, Morioka H,  Sakaguchi N, Qin C, Liu G.  Immunodominant SARS coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates. ACS Infectious Diseases 2016; 2(5): 361−376. https://doi.org/10.1021/acsinfecdis.6b00006
12. Wan Y, Shang J, Sun S, Tai W, Chen J, Geng Q, He L, Chen Y, Wu J, Shi Z, Zhou Y, Du L, Li F. 2020. Molecular mechanism for antibodydependent enhancement of coronavirus entry. J Virol 94:e02015-19. https://doi.org/10.1128/ JVI.02015-19. Editor Tom Gallagher, Loyola Univer  
13. WHO Expert Committee on Biological Standardization, Geneva, 21 to 25 October 2019  
14. Fan Wu, Aojie Wang, Mei Liu, Qimin Wang, Jun Chen, Shuai Xia, Yun Ling, Yuling Zhang, Jingna Xun, Lu Lu, Shibo Jiang, Hongzhou Lu, Yumei Wen, Jinghe Huang. Guidelines on the quality, safety and efficacy of respiratory syncytial virus vaccines Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications doi: https://doi.org/10.1101/2020.03.30.20047365  
15. Wu L-P, Wang N-C, Chang Y-H, Tian X-Y, Na D-Y, Zhang L-Y, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007;13(10):1562-4.
16. Yasui F, Kai C, Kitabatake M, Inoue S, Yoneda M, Yokochi S, Kase R, Sekiguchi S, Morita K, Hishima T, Suzuki H, Karamatsu K, Yasutomi Y, Shida H, Kidokoro M, Mizuno K, Matsushima K, Kohara M. Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV. The Journal of Immunology 2008; 181(9): 6337-6348. DOI: https://doi.org/10.4049/jimmunol.181.9.6337
17. Yuan M, Wu NC, Zhu X, Lee CC, So RT, Lv H, Mok CK, Wilson IA. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV. Science 2020 Apr 3. https://science.sciencemag.org/content/early/2020/04/02/science.abb7269#ref-