Indian Journal of Public Health

COMMENTARY
Year
: 2020  |  Volume : 64  |  Issue : 6  |  Page : 108--111

COVID-19 vaccine development and the way forward


Narendra Kumar Arora1, Manoja Kumar Das2,  
1 Executive Director, The INCLEN Trust International, New Delhi, India
2 Director Projects, The INCLEN Trust International, New Delhi, India

Correspondence Address:
Narendra Kumar Arora
The INCLEN Trust International, F1/5, Okhla Industrial Area, Phase 1, New Delhi - 110 020
India

Abstract

The whole globe is reeling under the COVID-19 pandemic now. With the scale and severity of infection, number of deaths and lack of any definite therapeutic armamentarium, the vaccine development has been accelerated at a never-before pace. A wide variety of vaccine technologies and platforms are being attempted. Out of the over 108 efforts, 100 are in preclinical and eight in Phase 1 or 2 trial stage. While the availability of newer technologies has facilitated development, there are several challenges on the way including limited understanding of the pathophysiology, targeting humoral or mucosal immunity, lack of suitable animal model, poor success of human severe acute respiratory syndrome/Middle East Respiratory Syndrome vaccines, limited efficacy of influenza vaccines, and immune exaggeration with animal coronavirus vaccines. With the current scenario with political, funding, research, and regulatory supports, if everything sails through smoothly, the successful vaccine is expected in 12–18 months. Modestly efficacious vaccine may be also a good achievement.



How to cite this article:
Arora NK, Das MK. COVID-19 vaccine development and the way forward.Indian J Public Health 2020;64:108-111


How to cite this URL:
Arora NK, Das MK. COVID-19 vaccine development and the way forward. Indian J Public Health [serial online] 2020 [cited 2021 Sep 21 ];64:108-111
Available from: https://www.ijph.in/text.asp?2020/64/6/108/285629


Full Text



 Introduction



Since its first appearance in Wuhan Province of China in December 2019, the novel coronavirus (severe acute respiratory syndrome [SARS]-CoV-2 or COVID-19) has infected over 3.9 million people with 274,488 deaths, across 212 countries globally. India with 35,043 cases as on April 30, 2020 stands the 16th position globally. While developed countries in Europe and Americas have suffered the most, the developing nations are expected to suffer severely from the COVID-19 infection, both from the health and socioeconomic aspects. The ongoing COVID-19 pandemic is the severest since the past Spanish Flu pandemic (1918–1919).

 The Virus and Host Response



The SARS-CoV-2 genome has close resemblance with SARS (80%) than Middle East respiratory syndrome (MERS)-CoV (54%) virus.[1] The spike (S) protein mediates attachment to host cells, and angiotensin-converting enzyme-2 functions as receptor for cellular penetration.[1] The S- and membrane (M) proteins induce neutralizing antibodies. The nucleocapsid (N) protein contains T-cell epitopes.[1] Droplets, close contact, and aerosol are considered as the main transmission modes.[2] Higher proportion (50%–78%) of asymptomatic infections have been observed.[3] The clinical manifestations vary widely from milder features to severe illnesses, primarily involve the respiratory system, but increasingly multisystem (cardiac, hepatic, neurological, vascular, and thromboembolism) involvement has been observed, several being immune mediated. The mortality rates range between 2.3 and 11% and more with patients aged >60 years and with underlying comorbidities.[4]

Among the symptomatic patients, antiviral neutralizing immunoglobulin G (IgG) antibodies were documented in 6–10 days.[5] No data are available on the period of SARS-CoV-2 acquired antibody and immunity. In the individuals infected with SARS or MERS, the antibody titers waned after 12–24 months.[6],[7] The preliminary reports indicate population seroprevalence of IgM or IgG antibodies range from 1.5% (the USA), 2.7% (the Netherlands), 15.5% (Germany), and 22% (Iran).[8],[9],[10],[11] In Switzerland community cohort, the IgG seroprevalence increased from 3.1% to 9.7% over 3 weeks.[12] Lower seroprevalence was observed among adults >60 years and under-five children.[11],[12] It is also no clear that whether these antibodies provide protection, its efficacy, duration, and in which type of population.

 Case Management and Control



No specific antiviral is available for SARS-CoV-2, although several repurposed drugs (chloroquine, hydroxychloroquine, remdesivir, lopinavir, ritonavir, and azithromycin, singly or in combination) and convalescent plasma, Igs, and plasma therapy are being used with variable success. In addition, some drugs (hydroxychloroquine and azithromycin) and immunomodulators are being used for prevention with some success. In absence of any definite treatment, public health preventive measures are being used for reducing transmission including isolation, contact tracing, face mask, personal protective equipment, and environmental disinfection.

 Efforts for Vaccine



The efforts for SARS-CoV-2 vaccine development are progressing at unprecedented scale and speed. The past experiences from SARS, MERS, and Ebola and availability of the next-generation vaccine technology platforms have accelerated the identification of potential candidates and development. A variety of platforms are being tried for the vaccine development [Table 1].[13] Some of the platforms are drawn from oncology and are relatively newer for vaccine. As of May 5, 2020, there are 108 efforts globally for COVID vaccine development including eight in Phase 1 or 2 clinical and 100 are in preclinical phases [Table 1].[13] The eight candidate vaccines moved to clinical evaluation phases involve ribonucleic acid (RNA), deoxyribonucleic acid (DNA), inactivated (without and with alum), and nonreplicating viral vectors, all leveraging the platforms used for other viral vaccines.[13],[14],[15]{Table 1}

The vaccines with attenuated viruses or replicating vectors are targeting inducement of mucosal immunity to reduce the mucosal infection and viral shedding. The RNA, DNA, and subunit vaccines aim for eliciting sufficient humoral neutralizing antibodies against proteins (S-protein as primary and M- and N-proteins as secondary targets) or receptor-binding domain to block viremia and systemic effects. The virus-like particles, subunits, recombinant viral vectors, and nucleic acid vaccines provide newer universal vaccine platforms amenable for introduction of new antigenic targets and are suitable for the new emerging viruses. These agents infect the host cells or induce antigenic proteins to generate both T-cell immune responses and antibodies. Several recombinant vectors from viruses (adenovirus, poxvirus, measles, parainfluenza, etc.) expressing the S- or N-proteins are also being explored. The route of administration shall depend on the type of vaccine. The dosage and schedule shall be determined by the mechanism, memory B- and T-cell responses, and exposure to SARS-CoV-2 infection. As per the available information, majority of the vaccines are being developed by private sector and from North America followed by China and Asia including eight Indian industries.[14],[16] Paralleling the development and facilitating regulatory adaptations are also being provided.

 Points for Consideration



Excessive and prolonged pro-inflammatory cytokine/chemokine responses have been observed in some SARS-CoV-2-infected individuals, known as the cytokine storm. The cytokine storm is proposed as the basis for acute respiratory distress syndrome, thromboembolism, and multi-organ dysfunctions, which lead to physiological deterioration and death.

A two-phase immune response has been observed with COVID infection. During the initial nonsevere stage, the adaptive immune response with antibody development helps in elimination of the virus. In some individuals with impaired protective immune response, the viral infection progresses causing cellular damage and immune-mediated cytokine storm leading to ARDS and other multisystem manifestations.[17] In view of the immune-mediated severe manifestations with COVID infection, the antibody-dependent enhancement has to be kept in radar, as experienced with dengue, measles, influenza, and respiratory syncytial virus vaccines.

Pilot convalescent plasma transfusions (CPTs) in COVID patients have demonstrated improvements in clinical features and pulmonary lesions with disappearance of viral RNA.[18] CPT is being used as passive immunotherapy at several centers globally. The benefit of CPT has raised possible development of immunotherapy using targeted immunoglobulin therapy. However, no study has evaluated whether the presence of antibodies against SARS-CoV-2 confers immunity to subsequent infection in humans.

 Lessons from the Past



Several vaccines for SARS-CoV-1 including S-protein-based, attenuated, and whole inactivated vaccines and with vectors were developed and tested in animals.[19] Most of these vaccines demonstrated protection. DNA-based candidate vaccines, one each for SARS and MERS reached Phase I clinical trial stage.[20] In some animals vaccinated with SARS-CoV vaccines, subsequent infection with other coronavirus or vaccine challenge was associated with enhanced disease and Th2-type immunopathology, suggesting hypersensitivity.[21] The currently licensed vaccines for preventing the coronavirus infections in animals and birds include the inactivated, attenuated, or live vector vaccines and have efficacy of 50%–100%.[15],[22]

The full pathophysiology and immune responses to SARS-CoV-2 are unclear and none of the animal models fully inform about the disease pathogenesis in humans, which pose challenge for vaccine development. Several animal models used to test SARS- and MERS-CoV vaccines include non-human primates (African green monkeys and macaques), hamsters, mice, and ferrets.[15]

 Challenges for Vaccine Development



The evidence based on COVID epidemiology, pathophysiology, host immune response, suitable antigen and antibody response, and postinfection protection are limited and evolving. Better characterization of the convalescent plasma may indicate the suitable antibody marker for protection and vaccine efficacy. Apart from waning antibodies over time, the immunological phenomena, immune enhancement, genetic changes, and immunosenescence in the elderly (as in influenza) should be considered for vaccines development and testing.[23],[24],[25] For testing vaccine efficacy, suitable marker (clinical and/or immunological) needs to be identified. In addition, the cold chain storage conditions are also to be considered to avoid the Ebola vaccine (storage under −60°C) like challenge.

 Timeline and Availability



With the continued investment and thrust, it is unlikely to have the SARS-CoV-2 vaccine before 12–18 months. With the naïve population status, almost all shall require the vaccine and more than one dose is needed to generate protective antibody. When a suitable vaccine becomes available, who shall get it first, developed countries or developing and poorer countries? Manufacturing adequate doses for majority of the world's population, affordable pricing and appropriate vaccine financing mechanisms, and public sector support shall be critical. Parallel production capacity building and technology sharing across the industries with appropriate academia-industry-funded partnership mechanism should be leveraged. Only few of the SARS and MERS vaccines moved to Phase I clinical trial and the enthusiasm and investment faded overtime. Without adequate funding and political support, the SARS-CoV-2 may also have similar fate, once the pandemic declines.

The vaccine should be offered to the corona warriors, individuals with underlying lung and systemic comorbidities and >60 years age, based on the availability. For assessing the vaccine effectiveness, appropriate risk and immunity categorization, the past infection with coronaviruses (SARS and MERS) and influenza must be considered. Furthermore, vaccine safety platform must be prepared to document the adverse events.

 Conclusion



The 1918 Spanish influenza pandemic, the most severe pandemic in history, which occurred in three waves over 2 years infected about one-third of the world's population and killed about 100 million people. The SARS-CoV-1 (2002–2004) and MERS (2012–2013) epidemics lasted for several months. The course of the SARS-CoV-2 pandemic is in progress. In absence of any definite drug, vaccine is critical. Although appears to be attractive, vaccine development is expected to face several challenges. The advancement in vaccine technologies, recent funding pledges, regulatory facilitations, and the speed exhibited have raised the hope. Better understanding of the pathophysiology, immunopathology, and suitable animal model shall enhance the vaccine development. It is to be seen whether the virus undergoes genetic transformation in future. Although in view of the current pandemic magnitude and severity, the investments and efforts are accelerated for vaccine development; it may be challenging to maintain the enthusiasm and pace of development once the episode subsides. We must be humble enough to admit knowledge gap about the virus. The vaccine development efforts may not be successful like several other viruses, or we may have vaccine(s) with modestly efficacy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3.
2Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020;382:1199-207.
3Day M. Covid-19: Four fifths of cases are asymptomatic, China figures indicate. BMJ 2020;369:m1375.
4Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review. Infect Dis Poverty 2020;9:29.
5Ju B, Zhang Q, Ge X, Wang R, Yu J, Shan S, et al. Potent Human Neutralizing Antibodies Elicited by SARS-CoV-2 Infection. Immunology; 2020. Available from: http://biorxiv.org/lookup/doi/10.1101/2020.03.21.990770. [Last accessed on 2020 May 11].
6Liu W, Fontanet A, Zhang P, Zhan L, Xin Z, Baril L, et al. Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. J Infect Dis 2006;193:792-5.
7Wu LP, Wang NC, Chang YH, Tian XY, Na DY, Zhang LY, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis 2007;13:1562-4.
8Bendavid E, Mulaney B, Sood N, Shah S, Ling E, Bromley-Dulfano R, et al. COVID-19 Antibody Seroprevalence in Santa Clara County, California. Epidemiology; 2020. Available from: http://medrxiv.org/lookup/doi/10.1101/2020.04.14.20062463. [Last accessed on 2020 May 11].
9Slot E, Hogema BM, Reusken CB, Reimerink JH, Molier M, Karregat JH, et al. Herd Immunity is Not a Realistic Exit Strategy During a COVID-19 Outbreak. Review; 2020. Available from: https://www.researchsquare.com/article/rs-25862/v1. [Last accessed on 2020 May 11].
10Streeck H, Schulte B, Kuemmerer B, Richter E, Hoeller T, Fuhrmann C, et al. Infection Fatality Rate of SARS-CoV-2 Infection in a German Community with a Super-Spreading Event. Infectious Diseases (except HIV/AIDS); 2020. Available from: http://medrxiv.org/lookup/do i/10.1101/2020.05.04.20090076. [Last accessed on 2020 May 11].
11Shakiba M, Hashemi Nazari SS, Mehrabian F, Rezvani SM, Ghasempour Z, Heidarzadeh A. Seroprevalence of COVID-19 Virus Infection in Guilan province, Iran. Infectious Diseases (except HIV/AIDS); 2020. Available from: http://medrxiv.org/lookup/do i/10.1101/2020.04.26.20079244. [Last accessed on 2020 May 11].
12Stringhini S, Wisniak A, Piumatti G, Azman AS, Lauer SA, Baysson H, et al. Repeated Seroprevalence of Anti-SARS-CoV-2 IgG Antibodies in a Population-Based Sample from Geneva, Switzerland. Infectious Diseases (except HIV/AIDS); 2020. Available from: http://medrxiv.org/lookup/doi/10.1101/2020.05.02.20088898. [Last accessed on 2020 May 11].
13World Health Organization. DRAFT Landscape of COVID-19 Candidate Vaccines. Geneva: World Health Organization; 2020. Available from: https://www.who.int/who-documents-detail/draft-landscape-of-covid -19-candi date-vaccine. [Last accessed on 2020 May 08].
14Thanh Le T, Andreadakis Z, Kumar A, Gómez Román R, Tollefsen S, Saville M, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov 2020;19:305-6.
15Saif LJ. Vaccines for COVID-19: Perspectives, prospects, and challenges based on candidate SARS, MERS, and animal coronavirus vaccines. Eur Med J 2020. pii: 200324.
16World Health Organization. WHO Solidarity Trial – Accelerating a Safe and Effective COVID-19 Vaccine. Geneva: World Health Organization. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-trial-accelerati ng-a-safe-and-effective-covid-19-vaccine. [Last accessed on 2020 May 02].
17Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection: The perspectives on immune responses. Cell Death Differ 2020;27:1451-4.
18Rajendran K, Krishnasamy N, Rangarajan J, Rathinam J, Natarajan M, Ramachandran A. Convalescent plasma transfusion for the treatment of COVID-19: Systematic review. J Med Virol 2020. doi: 10.1002/jmv.25961. Epub ahead of print. PMID: 32356910.
19Roper RL, Rehm KE. SARS vaccines: Where are we? Expert Rev Vaccines 2009;8:887-98.
20Padron-Regalado E. Vaccines for SARS-CoV-2: Lessons from Other Coronavirus Strains [published online ahead of print, 2020 Apr 23]. Infect Dis Ther 2020;1-20. doi:10.1007/s40121-020-00300-x.
21Tseng CT, Sbrana E, Iwata-Yoshikawa N, Newman PC, Garron T, Atmar RL, et al. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS One 2012;7:e35421.
22Sultan HA, Ali A, El Feil WK, Bazid AHI, Zain El-Abideen MA, Kilany WH. Protective efficacy of different live attenuated infectious bronchitis virus vaccination regimes against challenge With IBV variant-2 circulating in the Middle East. Front Vet Sci 2019;6:341.
23Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 2015;373:1195-206.
24Centers for Disease Control and Prevention. CDC Seasonal Flu Vaccine Effectiveness Studies (2004-2019). USA: Center for Disease Control. Available from: https://www.cdc.gov/flu/vaccines-work/effectiveness-studies.htm. [Last accessed on 2020 May 11].
25Rondy M, El Omeiri N, Thompson MG, Levêque A, Moren A, Sullivan SG. Effectiveness of influenza vaccines in preventing severe influenza illness among adults: A systematic review and meta-analysis of test-negative design case-control studies. J Infect 2017;75:381-94.