key: cord-0856993-ievuxa6k authors: Koirala, Archana; Jin Joo, Ye; Khatami, Ameneh; Chiu, Clayton; Britton, Philip N title: Vaccines for COVID-19: the current state of play date: 2020-06-18 journal: Paediatr Respir Rev DOI: 10.1016/j.prrv.2020.06.010 sha: 9ddf29ef66c2fc3b6ade550c4acf8da8d0d8f5a6 doc_id: 856993 cord_uid: ievuxa6k There is a strong consensus globally that a COVID-19 vaccine is likely the most effective approach to sustainably controlling the COVID-19 pandemic. An unprecedented research effort and global coordination has resulted in a rapid development of vaccine candidates and initiation of trials. Here, we review vaccine types, and progress with 10 vaccine candidates against SARS-CoV-2 – the virus that causes COVID-19 - currently undergoing early phase human trials. We also consider the many challenges of developing and deploying a new vaccine on a global scale, and recommend caution with respect to our expectations of the timeline that may be ahead. The reader will be able to: -Understand of the types of vaccine and vaccine platforms being developed for SARS-CoV-2. -Develop knowledge regarding the concerns around coronavirus vaccine development. -Appreciated the issues of rapid vaccine development in outbreak settings. -Ongoing progress of candidate vaccines through preclinical and clinical studies. -Ongoing detailed characterisation of the immunopathogenesis of COVID-19. -Implementation of large scale post marketing surveillance systems to monitor SARS-CoV2 vaccine safety. Introduction: COVID-19 is the disease caused by a novel betacoronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). The disease was first reported in December 2019 Wuhan, China [1] and the full genome was sequenced and published by January 05, 2020. [2] By March 11, 2020, COVID-19 had spread globally and was declared a pandemic, with, at the time of writing, June 6 th 2020, there has been over 6 million people infected and 380,000 deaths. [3] The disease primarily affects the respiratory tract and disease severity can range from very mild rhinorrhoea to severe acute respiratory distress syndrome and death. [4] [5] [6] A substantial minority of infections are asymptomatic. Non-respiratory symptoms such as anosmia, diarrhoea, rash, thromboembolic disorders, myocarditis and vasculitis have also been associated with COVID- 19 . [5] [6, 7] [8] [9] [10] [11] [12] [13] The median incubation period is estimated to be 5 days with a majority developing symptoms by 11.5 days. [14] COVID-19 patients have been shown to excrete viral nucleic acid at highest levels at the onset of symptoms [15] . This, and other epidemiological data [16] suggests transmissibility within an as yet undefined pre-symptomatic period. [16] Clinical deterioration is usually delayed into the second week of illness and associated with laboratory features of an immune-mediated cytokine storm causing widespread inflammation and disseminated intravascular coagulation, usually with low level viraemia. [17, 18] The case fatality rate (death amongst persons with disease) is consistently reported to be age dependent, with a higher percentage in elderly (aged >70 years) cases dying, although other factors are also associated with intensive care admission and mortality [9] [6] [19] including sex (male>female), hypertension, obesity and diabetes. The reported case fatality rates [CFR] have been between 0.82% and 9.64%, with variability in CFR likely due to the testing frequency and access as well as other health system capacity factors in different locations. [20] The infection fatality rate (IFT; death amongst all people infected -asymptomatic and not tested) is a better estimate of population mortality and is modelled to be between 0.1% to 0.41% [20] SARS-CoV-2 is one of three coronaviruses that may cause severe respiratory diseases, including In addition to these novel epidemic viruses with zoonotic origins, there are four other endemic human coronaviruses in circulation, HCoV2-229E, -HKU1, -NL63 and -OC43 all predominantly causing mild symptoms of the common cold. [21] History of vaccines for Coronaviruses: Coronaviruses have a large (30+ kb) single-stranded positive sense RNA genome encased by a helical nucleocapsid (N) and an outer envelope comprised of matrix protein (M), envelope protein (E) and spike proteins (S). [22] The S protein, which naturally occurs in a trimeric form, contains the receptor-binding domain (RBD) responsible for binding onto the angiotensin converting enzyme 2 (ACE2) and entry into the cell (Figure 1 ). In SARS-CoV, of all the structural proteins, S protein was found to elicit neutralising antibody and is a major target antigen for vaccine development. [23] [ 24] There have been difficulties in the development of coronavirus vaccines historically. Coronavirus vaccines in animal models that mimic human disease have been immunogenic but generally not shown to effectively prevent acquisition of disease [25] . Further, there is a concern that vaccination, as with natural coronaviral infection, may not induce long lived immunity and re-infection may be possible. [26] In some ways more concerning has been vaccine associated disease enhancement. Previous use of coronavirus vaccines (SARS-CoV and MERS-CoV) in some animal models raised safety concerns regarding Th2 mediated immunopathology. [27] Mice vaccinated with two inactivated whole virus vaccines, a recombinant DNA spike protein vaccine or a virus-like particle vaccine developed lung pathology including eosinophilic infiltration 2 days after being challenged with SARS-CoV which were not seen in the lungs of challenged unvaccinated mice. [28] Similar lung immunopathology was observed in several other studies, particularly in aged mice compared to younger mice [29] that were challenged following vaccination [30, 31] Context: Developing and scaling-up mass production of a vaccine rapidly in a global pandemic setting is challenging as it requires many activities to be well-coordinated and occurring in parallel, in contrast to the usual decade long, sequential process with pre-clinical testing, phased clinical trials, planned production and distribution. These challenges result in an aggregation of invested resources and Even if sustained immunity is attained after infection by SARS-CoV2, estimates are that 60-70% of a population would need to be immune to achieve herd immunity against SARS-CoV2. [70] The safest and most controlled way for effective and sustainable prevention of COVID-19 in a population is to have an efficacious and safe vaccine and the majority of the population successfully vaccinated. In addition, the vaccine should also be readily mass-produced inexpensively, and be easily transportable with minimal cold chain requirements to have global utility. Immunity after primary COVID-19 infection seems to protect against re-infection in primate models and is likely to occur in humans [71] ; whether this can be mimicked in vaccines and for how long immunity may last is still uncertain. Following SARS-CoV infection, IgG and Neutralising Ab was detectable for 1 to 3 years following infection which suggests that vaccine-induced protection is unlikely to be long-lasting and may require re-immunization. There has never been a more rapid pace to vaccine development. The pandemic situation has been a challenge and a trigger to reconsidering the usual approaches to regulatory assessment and licensing processes. Vaccine companies are showing willingness to commit to scaled-up production prior to definitive phase 3 trial results. [79] The implementation of high quality, aligned surveillance for COVID-19 across multiple regions concurrently with vaccine deployment is critical both for evaluating the real-world effectiveness of a new vaccine against SARS-CoV-2, but also for monitoring its safety in so-call 'post-marketing' surveillance. The association of rotavirus vaccines with intussusception in children was only detected following licensure and deployment of these vaccines. A novel coronavirus from patients with pneumonia in China A new coronavirus associated with human respiratory disease in China Clinical characteristics of coronavirus disease 2019 in China Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet Covid-19 in critically ill patients in the Seattle region-case series Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. The American journal of gastroenterology Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The lancet Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: a cross-sectional study A pneumonia outbreak associated with a new coronavirus of probable bat origin SARS-CoV-2 induced diarrhoea as onset symptom in patient with COVID-19 Cutaneous manifestations in COVID-19: a first perspective The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients Temporal dynamics in viral shedding and transmissibility of COVID-19 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The lancet Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis Global COVID-19 Case Fatality Rates Coronavirus Infections in Children Including COVID-19: An Overview of the Epidemiology, Clinical Features, Diagnosis, Treatment and Prevention Options in Children Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment Contributions of the structural proteins of severe acute respiratory syndrome coronavirus to protective immunity Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein SARS vaccines: where are we? Expert Rev Vaccines Human coronavirus reinfection dynamics: lessons for SARS-CoV A decade after SARS: strategies for controlling emerging coronaviruses Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus Vaccine efficacy in senescent mice challenged with recombinant SARS-CoV bearing epidemic and zoonotic spike variants A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge Induction of immune responses and protection in mice against rabies using a self-replicating RNA vaccine encoding rabies virus glycoprotein. Veterinary microbiology Advances in mRNA Vaccines for Infectious Diseases A SARS DNA vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a Phase I clinical trial. Vaccine Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial. The Lancet Infectious Diseases Identifier: NCT03721718. Evaluate the Safety, Tolerability and Immunogenicity Study of GLS-5300 in Healthy Volunteers 2020 Safety and immunogenicity from a phase I trial of inactivated severe acute respiratory syndrome coronavirus vaccine. Antiviral therapy World Health Organization, DRAFT landscape of COVID-19 candidate vaccines Identifier: NCT04283461. Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) Harnessing the beneficial heterologous effects of vaccination Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Archives of Disease in Childhood Early BCG-Denmark and neonatal mortality among infants weighing< 2500 g: a randomized controlled trial Nonspecific Effects of Oral Polio Vaccine on Diarrheal Burden and Etiology Among Bangladeshi Infants Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries Considering BCG vaccination to reduce the impact of COVID-19. The Lancet Identifier: NCT04327206. BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE) 2020 Identifier: NCT04328441. Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine (BCG-CORONA) Global Polio Eradication Initiative. The use of oral polio vaccine (OPV) to prevent SARS-CoV2 Herd Immunity: Understanding COVID-19. Immunity, 2020 Reinfection could not occur in SARS-CoV-2 infected rhesus macaques Duration of antibody responses after severe acute respiratory syndrome. Emerging infectious diseases Two-year prospective study of the humoral immune response of patients with severe acute respiratory syndrome. The Journal of infectious diseases Disappearance of Antibodies to SARS-Associated Coronavirus after Recovery Longitudinal profiles of immunoglobulin G antibodies against severe acute respiratory syndrome coronavirus components and neutralizing activities in recovered patients Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. The Lancet Moderna Announces Positive Interim Phase 1 Data for its mRNA Vaccine (mRNA-1273) Against Novel Coronavirus Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation study. The Lancet COVID-19 vaccine development pipeline gears up. The Lancet Update on WHO Solidarity Trial -Accelerating a safe and effective COVID-19 vaccine NIH to launch public-private partnership to speed COVID-19 vaccine and treatment options Value of post-licensure data on benefits and risks of vaccination to inform vaccine policy: The example of rotavirus vaccines Rotavirus vaccination and intussusception -Science, surveillance, and safety: A review of evidence and recommendations for future research priorities in low and middle income countries. Human vaccines & immunotherapeutics Vaccine confidence plummets in the Philippines following dengue vaccine scare: why it matters to pandemic preparedness Initial impacts of global risk mitigation measures taken during the combatting of the COVID-19 pandemic World Health Organization and Global Polio Eradication Initiative, Polio endgame strategy 2019-2023: eradication, integration, certification and containment A Supply and Demand Management Perspective on the Accelerated Global Introductions of Inactivated Poliovirus Vaccine in a Constrained Supply Market. The Journal of Infectious Diseases Chinese Clinical Trial Registry. ChiCTR2000030906 A phase I clinical trial for recombinant novel coronavirus (2019-COV) vaccine (adenoviral vector) 2020 Identifier: NCT04313127. Phase I Clinical Trial of a COVID-19 Vaccine in 18-60 Healthy Adults (CTCOVID-19) 2020 Chinese Clinical Trial Registry. ChiCTR2000031781 A randomized, double-blinded, placebocontrolled phase II clinical trial for Recombinant Novel Coronavirus (2019-nCOV) Vaccine (Adenovirus Vector) 2020 Identifier: NCT04341389. A Phase II Clinical Trial to Evaluate the Recombinant Vaccine for COVID-19 (Adenovirus Vector) (CTII-nCoV) 2020 Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial Identifier: NCT04324606. A Study of a Candidate COVID-19 Vaccine (COV001) Identifier: NCT04352608. Safety and Immunogenicity Study of Inactivated Vaccine for Prophylaxis of SARS CoV-2 Infection (COVID-19) Identifier: NCT04383574. Safety and Immunogenicity Study of Inactivated Vaccine for Prevention of SARS-CoV-2 Infection(COVID-19) Chinese Clinical Trial Registry. ChiCTR2000031809 A randomized, double-blind, placebo parallel-controlled phase I/II clinical trial for inactivated Novel Coronavirus Pneumonia vaccine (Vero cells) Chinese Clinical Trial Registry. ChiCTR2000031809 A randomized, double-blind, placebo parallel-controlled phase I/II clinical trial for inactivated Novel Coronavirus Pneumonia vaccine (Vero cells) Identifier: NCT04368988. Evaluation of the Safety and Immunogenicity of a SARS-CoV-2 rS (COVID-19) Nanoparticle Vaccine With/Without Matrix-M Adjuvant A Multi-site Phase I/II, 2-Part, Dose-Escalation Trial Investigating the Safety and Immunogenicity of four Prophylactic SARS-CoV-2 RNA Vaccines Against COVID-2019 Using Different Dosing Regimens Identifier: NCT04336410 Identifier: NCT04334980 Serological Approaches for COVID-19: Epidemiologic Perspective on Surveillance and Control