Written by: Gunnveig Grødeland, PhD, University of Oslo and Oslo University Hospital.

Effective control of Covid-19 is dependent upon development of protective and safe vaccines. At present, there are many different vaccine formats against SARS-CoV-2 in clinical development, with the more advanced already in clinical Phase III studies. A remaining challenge, however, is that we still do not have a clear understanding of what constitutes the most relevant type of immunity for protection against Covid-19, and what would be the best strategy for induction of such protection.

A serological survey of over 35,000 households in Spain has demonstrated that an overall 5% of the population has antibodies against SARS-CoV-2, with a higher prevalence of 10% around Madrid and lower in coastal areas (1). Spain has been one of the more severely Covid-19 affected countries in Europe. The fairly low incidence of antibodies in the Spanish population therefore implies that we cannot rely on herd immunity to develop naturally from the present pandemic. Further, the prevalence of SARS-CoV-2 specific antibodies in populations from the epicenters of New York and Lombardy has been estimated to be about 20-25% (2,3). It is not yet clear which antigens and epitopes the induced antibodies are directed against, but there are indications that the antibodies may have a limited capacity for neutralization (4).

During the previous SARS-CoV-1 outbreak in 2002/03, it was demonstrated that antibodies induced against immunodominant sites of the Spike protein were not neutralizing (5). It is also known that when neutralizing antibodies are induced they typically bind to the receptor binding domain of Spike, but also that such antibodies could potentially induce conformational changes in Spike due to mimicking of the ACE-2 receptor and as such potentially enhance viral infection (6). Careful design would therefore be needed for utilization of Spike as a vaccine antigen.

While most vaccines presently in development against SARS-CoV-2 aim for induction of antibodies, cellular immunity can also award protection against disease. Interestingly, a large part of the population have T cells that are reactive against different SARS-CoV-2 proteins even in the absence of a SARS-CoV-2 infection. These T cells are mostly CD4+, and likely originated from previous infections with the “common cold” coronaviruses (7,8). However, it is not yet clear to what degree their presence can reduce development of severe Covid-19 disease.

How should we proceed with vaccine development in a situation where the correlate of protection is not clear?

Pandemics may emerge when a novel pathogen has acquired the ability to transmit efficiently from human to human. As is the case for SARS-CoV-2, we should expect many unknowns when a new pandemic erupts. Vaccination remains the best preventive strategy, but how can one efficiently design vaccines when it is not clear what type of immune responses will be more important for protection? The only answer today is to simultaneously develop many different vaccine formats, compare their strengths and weaknesses, and select the best-fit candidate for vaccination of the population. For this to work, it is important that researchers share both promising and negative results for their particular vaccine format. It is my hope that this strategy will secure a vaccine ready to be large-scale deployed against SARS-CoV-2 during 2021.

We can be certain that SARS-CoV-2 will not be the last pandemic challenge facing the world. It is still unclear what will happen during this fall, but alongside taming the present outbreak, we should try to generate knowledge and strategies that may be of use for quenching the next pandemic emergence caused by an unknown pathogen X. This includes both strategies for managing transmission in society, development of treatment strategies that can be used for limiting replication across different viral families, as well as development of vaccine platforms that can be readily adapted for tailored induction of particular types of immunity.

A new era for subunit vaccines?

Interestingly, a majority of the vaccine formats presently in development against SARS-CoV-2 are subunit vaccines, meaning that they contain only selected viral antigens. At present, there are no genetic subunit vaccine licensed for use in humans, but there are a few protein based subunit vaccines available (e.g., Flublok by Sanofi, Recombivax by Merck).

Subunit vaccines have typically been hampered by reduced immunogenicity, necessitating the combined use of an adjuvant or alternative strategies for enhancing vaccine efficacy. However, their safety profiles and ease of production nevertheless makes subunit vaccines ideal for pandemic prevention.

The large amount of research presently going into development and clinical evaluation of different subunit vaccines is unprecedented. Thus, the ongoing SARS-CoV-2 pandemic may turn out to be the breaking point where subunit vaccines establish themselves as the preferred alternative to conventional inactivated or attenuated vaccines.

Subunit vaccines rely on rational selection and design of selected antigens. As such, immune responses can be steered towards antigenic regions more relevant for development of protective immunity. The better we understand human immunology, the better subunit vaccines we can design. For the future, we could be able to assign the relevant correlate of protection by examining shared pathogen traits, and then design vaccines specifically tailored for induction of the corresponding type of immunity. In the meantime, we will likely fare better by aiming a bit more broadly, and develop subunit vaccines that can induce both antibody and T cell responses.

References

1.    Pollan, M., B. Perez-Gomez, R. Pastor-Barriuso, J. Oteo, M. A. Hernan, M. Perez-Olmeda, J. L. Sanmartin, A. Fernandez-Garcia, I. Cruz, L. N. Fernandez de, M. Molina, F. Rodriguez-Cabrera, M. Martin, P. Merino-Amador, P. J. Leon, J. F. Munoz-Montalvo, F. Blanco, and R. Yotti. 2020. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet.

2.    Percivalle, E., G. Cambie, I. Cassaniti, E. V. Nepita, R. Maserati, A. Ferrari, M. R. Di, P. Isernia, F. Mojoli, R. Bruno, M. Tirani, D. Cereda, C. Nicora, M. Lombardo, and F. Baldanti. 2020. Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020. Euro. Surveill 25.

3.    Stadlbauer D, Tan J, Jiang K, Hernandez M.M, Fabre S, Amanat F, Teo C, Arunkumar G, McMahon M, Jhang J, Nowak MD, Simon V, Sordillo EM, Bakel H, and Krammer F. 2020. Seroconversion of a city: Longitudinal monitoring of SARS-CoV-2 seroprevalence 1 in New York City. medRxiv preprint.

4.    Robbiani, D. F., C. Gaebler, F. Muecksch, J. C. C. Lorenzi, Z. Wang, A. Cho, M. Agudelo, C. O. Barnes, A. Gazumyan, S. Finkin, T. Hagglof, T. Y. Oliveira, C. Viant, A. Hurley, H. H. Hoffmann, K. G. Millard, R. G. Kost, M. Cipolla, K. Gordon, F. Bianchini, S. T. Chen, V. Ramos, R. Patel, J. Dizon, I. Shimeliovich, P. Mendoza, H. Hartweger, L. Nogueira, M. Pack, J. Horowitz, F. Schmidt, Y. Weisblum, E. Michailidis, A. W. Ashbrook, E. Waltari, J. E. Pak, K. E. Huey-Tubman, N. Koranda, P. R. Hoffman, A. P. West, Jr., C. M. Rice, T. Hatziioannou, P. J. Bjorkman, P. D. Bieniasz, M. Caskey, and M. C. Nussenzweig. 2020. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature.

5.    He, Y., Y. Zhou, H. Wu, B. Luo, J. Chen, W. Li, and S. Jiang. 2004. Identification of immunodominant sites on the spike protein of severe acute respiratory syndrome (SARS) coronavirus: implication for developing SARS diagnostics and vaccines. J. Immunol. 173: 4050-4057.

6.    Yang, Z. Y., H. C. Werner, W. P. Kong, K. Leung, E. Traggiai, A. Lanzavecchia, and G. J. Nabel. 2005. Evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses. Proc. Natl. Acad. Sci. U. S. A 102: 797-801.

7.    Grifoni, A., D. Weiskopf, S. I. Ramirez, J. Mateus, J. M. Dan, C. R. Moderbacher, S. A. Rawlings, A. Sutherland, L. Premkumar, R. S. Jadi, D. Marrama, A. M. de Silva, A. Frazier, A. F. Carlin, J. A. Greenbaum, B. Peters, F. Krammer, D. M. Smith, S. Crotty, and A. Sette. 2020. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181: 1489-1501.

8.    Le Bert N, Tan TA, Kunasegaran K, Tham CYL, Hafezi M, Chia A, Chng M, Lin M, Tan N, Linster M, Chia WN, Chen MIC, Wang LF, Ooi EE, Lalimuddin S, Tambyah PA, Low JGH, Tan YJ, and Bertoletti A. 2020. Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals. bioRxiv preprint.

Biopharmaceutical companies, government agencies, academic institutions and non-profits located world-wide have mobilized in an unprecedented effort to develop interventions that are effective against SARS-CoV-2, the virus that causes COVID-19. This global pandemic, however, affects people of all ages and every health status. As a consequence, we need a wide array of medicines, as well as vaccines, to ensure the right intervention is given to the right person. And we need these interventions as quickly as possible.

In Part 1 of ‘Coronavirus in the crosshairs’, we focused on early clinical studies for small molecule drugs that were re-purposed, i.e., drugs that were already approved or in clinical studies for another disease, but were tested for efficacy in COVID-19 patients. In Part 2 of this series, we focus on vaccines currently in clinical study. Part 3 will focus on the use of anti-SARS-CoV-2 polyclonal antibodies found in convalescent plasma as a treatment for COVID-19, and Part 4 will examine efforts to quickly discover anti-SARS-CoV-2 antibody therapeutics.

Vaccines in preclinical and clinical development

The World Health Organization has compiled a list of SARS-CoV-2 vaccine initiatives that, as of March 20, 2020, included 42 vaccines in preclinical development and 2 vaccines in human Phase 1 studies, National Institutes of Health (NIH)/Moderna’s mRNA-1273 vaccine and CanSino Biological Inc./Beijing Institute of Biotechnology’s adenovirus Type 5 vector (Ad5-nCoV) vaccine.

In addition, the Regulatory Affairs Professionals Society is maintaining the Regulatory Focus COVID-19 Tracker, which is a resource for information on COVID-19 vaccine development that is updated weekly.

mRNA-1273 vaccine candidate

mRNA-1273 is a novel lipid nanoparticle-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike protein of SARS-CoV-2. The  vaccine candidate has shown promise in animal models. Manufacturing of mRNA-1273 for the Phase 1 study (NCT04283461) was supported by the Coalition for Epidemic Preparedness Innovations. On March 16, 2020, NIH announced the study, which will assess the safety and immunogenicity of mRNA-1273,  had started. A total of 45 adults between the ages of 18 to 55 years will be enrolled, and the estimated primary completion date of the study is June 1, 2021. According to the protocol, however, the immunogenicity data will start being collected by mid-May 2020. Moderna announced on March 23, 2020 that, under emergency use, a vaccine could be available to some people, possibly including healthcare professionals, in the fall of 2020, although a commercially-available vaccine is not likely to be available for at least 12-18 months.

Enrollment will occur at the Kaiser Permanente Washington Health Research Institute. Forty-five healthy adults will be administered one of three doses (25 microgram [mcg], 100 mcg, 250 mcg). They will receive an intramuscular injection of mRNA-1273 on Days 1 and 29 in the deltoid muscle, and will be followed through 12 months post second vaccination (Day 394). The first four participants will receive one injection with the low dose, and the next four participants will receive the 100 mcg dose. Investigators will review safety data before vaccinating the remaining participants in the 25 and 100 mcg dose groups and before participants receive their second vaccinations. Another safety review will be done before participants are enrolled in the 250 mcg cohort. Follow-up visits will occur 1, 2 and 4 weeks post each vaccination, as well as 3, 6 and 12 months post second vaccination.

The primary objective is to evaluate the safety and reactogenicity and the secondary objective is to evaluate the immunogenicity as measured by IgG ELISA to the 2019-nCoV S protein following a 2-dose vaccination schedule of mRNA-1273 at Day 57.

Ad5-nCoV vaccine candidate

On March 17, 2020, CanSino Biologics Inc. announced that its recombinant novel coronavirus vaccine Ad5-nCoV, co-developed with Beijing Institute of Biotechnology, has been approved to enter into a Phase 1 clinical trial. The Phase 1 ChiCTR2000030906 study was listed as recruiting patients when its record was accessed March 23, 2020; NCT04313127 is assumed to be the same study.

The single-center, open and dose-escalation Phase 1 clinical trial will evaluate Ad5-nCoV in healthy adults aged between 18 and 60 years. Three doses will be evaluated, with a total of 108 patients (36 per study arm) receiving a low (5E10 vp Ad5-nCoV), medium (1E11 vp Ad5-nCoV) or high (1.5E11vp Ad5-nCoV) dose of vaccine. Various types of antibody responses will be measured at Day 14, 28, and months 3 and 6 post injection.

Other vaccine candidates

Clinical studies of two additional vaccine candidates, Covid-19 aAPC Vaccine and Covid-19 Synthetic Minigene Vaccine, are listed on clinicaltrials.gov as recruiting patients (NCT04299724 and NCT04276896, respectively), although the status of these initiatives could not be confirmed as of March 23, 2020. Both vaccine candidates are sponsored by Shenzhen Geno-Immune Medical Institute, Shenzhen Third People’s Hospital, and Shenzhen Second People’s Hospital.

Coronavirus image from: CDC/ Alissa Eckert, MS; Dan Higgins, MAMS