key: cord-279260-tdvb0fhv authors: Lv, Huibin; Wu, Nicholas C.; Mok, Chris K. P. title: COVID‐19 vaccines: knowing the unknown date: 2020-05-21 journal: Eur J Immunol DOI: 10.1002/eji.202048663 sha: doc_id: 279260 cord_uid: tdvb0fhv Vaccine development against SARS‐CoV‐2 has drawn attention around the globe due to the exploding pandemic. Although COVID‐19 is caused by a new coronavirus, SARS‐CoV‐2, previous research on other coronavirus vaccines, such as FIPV, SARS and MERS, has provided valuable information for the rapid development of COVID‐19 vaccine. However, important knowledge gaps remain – some are specific to SARS‐CoV‐2, others are fundamental to immunology and vaccinology. Here we discuss areas that need to be addressed for COVID‐19 vaccine development, and what can be learned from examples of vaccine development in the past. Since the beginning of the outbreak, the research progress on COVID‐19 has been remarkable. We are therefore optimistic about the rapid development of COVID‐19 vaccine. This article is protected by copyright. All rights reserved namely inactivated virus, lipid nanoparticle (LNP)-encapsulated mRNA, and plasmid DNA, are in phase I clinical trials (https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf). Other platforms, such as live attenuated virus, protein subunit, are also being evaluated at the pre-clinical stage. Although there is an urgent need for these vaccines to become available, several critical features of the COVID-19 vaccine will need to be assessed, based on the experience from previous vaccine development for Feline-CoVs, MERS-CoV, SARS-CoV and other viruses ( Figure 1 ). It is highly desirable that a potential vaccine will induce a potent antibody response as well as long-term . Identifying the epitopes that are targeted by these antibodies will be crucial to determine the antigenic sites on the spike of SARS-CoV-2. Although traditionally an effective vaccine should mainly aim to elicit a high titer of neutralizing antibodies, it was found that some non-neutralizing antibodies could provide in vivo protection through antibody dependent cell-mediated cytotoxicity (ADCC) [15] . Thus, it will be interesting to distinguish the functions of the antibodies isolated from volunteers in clinical trials in order to understand in molecular terms vaccines' effectiveness. It is also important to note that T-cell immunity was found to be elicited by SARS-CoV or MERS-CoV DNA vaccines (both express trimeric spike protein) [7, 9] . These results imply that using SARS-CoV-2 spike protein as immunogen may also elicit cellular immune response, in addition to humoral immune response. There is a concern that some antibodies elicited by the SARS-CoV-2 vaccine may cause an adverse effect such as antibody-dependent enhancement (ADE) or enhanced respiratory disease (ERD) [ suggesting such a potential complication may not be a concern, at least for RBD-based SARS-CoV-2 vaccine development [23]. To enhance the magnitude and quality of the adaptive response, adjuvants are included in some vaccination formulations [24] . Different adjuvants drive different immunological signatures and, hence, are optimal for protection against different pathogens [25] . For example, adjuvants can modulate the ratio of T helper 1 (Th1) and T helper 2 (Th2) responses, increase the generation of memory cells, and alter the breadth and affinity of the response [24] . Determining which adjuvants can enhance protective vaccine response to SARS-CoV-2 will be important. Because immune responses in different age groups are not the same, optimal vaccination strategy may be varied for different age groups [26] . For example, the MF59-adjuvanted influenza vaccine, Fluad, is only licensed and approved for adults aged 65 years and older, to elicit a higher protective immune response in the elderly This article is protected by copyright. All rights reserved. (https://www.cdc.gov/flu/prevent/adjuvant.htm). As it is clear that the mortality rate in the elderly is the highest among the COVID-19 patients, a specific vaccination strategy for this group will need to be considered during vaccine development. To accelerate vaccine development, animal infection models for SARS-CoV-2 are needed. Although macaques show COVID-19-like disease upon SARS-CoV-2 infection, the non-human primate model is usually not readily accessible to most laboratories [27] . Ferrets and golden Syrian hamster are presented as alternatives, as all show mild disease signs and virus shedding after challenge with SARS-CoV-2 [28, 29] , and are usually more widely available than non-human primates. Nonetheless, mouse is the most commonly used animal model during vaccine development in general. Although wild type mouse is not susceptible to the infection of SARS-CoV-2, transgenic mice that express the human angiotensin-converting enzyme 2 (hACE2) receptor, which was previously established for SARS-CoV study [30] , showed significant pathogenicity upon the infections of SARS-CoV-2 [31] . Expressing hACE2 through adenoviral transduction may provide another possible approach to generate a mouse model for SARs-CoV-2 infection. The feasibility of this approach is suggested by a previous study that used adenoviral transduction to generate a mouse model for MERS-CoV infection [32] . The advantage of this approach is that it can be applied to multiple genetic backgrounds including outbred mice. These animal models are thus suitable to evaluate vaccine candidates in preclinical settings. There is also a pressing need to define correlates of protection, which have the additional benefit of serving as a benchmark for vaccine evaluation without the need for challenge studies, an approach that has been used for many different pathogens [33] . A typical example is influenza vaccine, where a hemagglutination inhibition (HAI) titer of ≥1:40 is a surrogate of protection [34] . However, the exact serological parameters that provide best correlation with protection against SARS-CoV-2 infection will need to be investigated. On a related note, evaluating the neutralizing antibody titer against This article is protected by copyright. All rights reserved. Therefore, pseudovirus assays that can be performed in a BSL2 setting are also valuable for vaccine development [35, 36] . Zoonotic coronaviruses are likely to be a continuous threat [37] . Although generation of a pan-coronaviruses vaccine seems unlikely, owing to the high genetic diversity among different genera, it might be possible to develop a pan-betacoronavirus vaccine to prevent the potential risk from new subtypes identified in bats, pangolins or other species [37] . Indeed, cross-reactivity between different betacoronaviruses has been found in human samples. For example, a conserved CD4 T-cell epitope can mediate cross-reactive protection between SARS-CoV and MERS-CoV [38] . In addition, our recent study has revealed a conserved antibody epitope shared by SARS-CoV-2 and SARS-CoV [39] . These results indicate a potential roadmap for the development of universal vaccine against coronaviruses. Although it is not possible to predict, at this moment, the strain of the next coronavirus that will jump species, continuing exploration of the B-cell repertoire to identify cross-reactive epitopes will be important for the development of a coronavirus vaccine with high breadth of coverage. Taken together, while therapeutic approaches for COVID-19 are urgently needed (reviewed in [40] ) given the increasing number of active cases, the ultimate goal of establishing sterilizing immunity in This article is protected by copyright. All rights reserved. uninfected individuals will require an SARS-CoV-2 vaccine. We are confident that the rapid and collaborative efforts among researchers around the globe will offer an effective countermeasure to COVID-19 in the near future. 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Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV Establishment This article is protected by copyright. All rights reserved. and validation of a pseudovirus neutralization assay for SARS-CoV-2 A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence Cells Mediate Protective Immunity against Emerging Respiratory Coronaviruses. Immunity A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV Controlled modulation of innate immunity to prevent and treat COVID-19 disease We thank Profs Roberto Bruzzone and Stanley Perlman for helpful discussions. The authors declare no financial or commercial conflict of interest.This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. An ideal COVID-19 vaccine should offer long-term protection with no adverse effect. The current status of COVID-19 vaccine development and factors that need to be considered are discussed.