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Saturday, May 30, 2020

A strategic approach to COVID-19 vaccine R&D

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Science  29 May 2020:
Vol. 368, Issue 6494, pp. 948-950
DOI: 10.1126/science.abc5312
There is an unprecedented need to manufacture and distribute enough safe and effective vaccine to immunize an extraordinarily large number of individuals in order to protect the entire global community from the continued threat of morbidity and mortality from severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The global need for vaccine and the wide geographic diversity of the pandemic require more than one effective vaccine approach. Collaboration will be essential among biotechnology and pharmaceutical companies, many of which are bringing forward a variety of vaccine approaches (1). The full development pathway for an effective vaccine for SARS-CoV-2 will require that industry, government, and academia collaborate in unprecedented ways, each adding their individual strengths. We discuss one such collaborative program that has recently emerged: the ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) public-private partnership. Spearheaded by the U.S. National Institutes of Health (NIH), this effort brings together the strengths of all sectors at this time of global urgency. We further discuss a collaborative platform for conducting harmonized, randomized controlled vaccine efficacy trials. This mechanism aims to generate essential safety and efficacy data for several candidate vaccines in parallel, so as to accelerate the licensure and distribution of multiple vaccine platforms and vaccines to protect against COVID-19 (coronavirus disease 2019).
We currently know little about what constitutes a protective immune response against COVID-19. Data from SARS-CoV-1 patients as well as recently infected SARS-CoV-2 patients document relatively high levels of immune responses after infection, especially antibody responses to the surface (spike) protein that mediates entry into host cells. However, in vivo data on the type or level of immunity required to protect from subsequent re-infection, and the likely duration of that protection, are currently unknown. In animal models of SARS-CoV-1, immunization with recombinant subunit proteins and viral- and nucleic acid–vectored vaccines, as well as passive transfer of neutralizing antibodies to the spike protein, have been shown to be protective against experimental infection (2, 3). Endpoints vary from protection of infection to modification of viral replication and disease. These data bring optimism that a highly immunogenic vaccine will elicit the magnitude and quality of antibody responses required for protection. The role that T cell immunity plays in preventing acquisition or amelioration of early disease, either in animal challenge models or in human coronavirus disease, is unclear (4); this constitutes another reason why a diversity of vaccine approaches must be pursued.
A high degree of safety is a primary goal for any widely used vaccine, and there is theoretical risk that vaccination could make subsequent SARS-CoV-2 infection more severe. This has been reported for feline coronaviruses and has been observed in some vaccine-challenge animal models of SARS-CoV-1 (5). These preclinical data suggest that the syndrome of vaccine-associated enhanced respiratory disease results from a combination of poorly protective antibodies that produce immune complex deposition together with a T helper cell 2 (TH2)–biased immune response. The potential mechanism behind vaccine-induced immune enhancement and the means to minimize this risk have recently been reviewed (6). It will be important to construct conformationally correct antigens to elicit functionally effective antibodies—a lesson learned from vaccine-induced enhanced lower respiratory illness among infants receiving a formalin-inactivated respiratory syncytial virus (RSV) vaccine. Animal models of SARS-CoV-2 infection are currently being developed, and these models can be used to better understand the immune responses associated with protection (7).

Clinical and Immunological Endpoints

The primary endpoint for defining the effectiveness of a COVID vaccine also requires discussion. The two most commonly mentioned are (i) protection from infection as defined by seroconversion, and (ii) prevention of clinically symptomatic disease, especially amelioration of disease severity, including the frequency of disease requiring high-intensity medical care with some assessment of a decrease in hospitalization. This requires the close evaluation of the effect of vaccination on the severity of COVID-19 disease in a wide variety of epidemiological and medical settings among both younger and elderly populations as well as underserved minorities. All of these issues need to be evaluated in the context of these initial efficacy trials. Achieving these endpoints could also be associated with reduced transmissibility on a population basis.
Primary endpoints that involve reduction of disease require greater numbers of enrollees into trials, given that asymptomatic infection is estimated to be 20 to 40% of total cases of COVID-19 (8). Initial efficacy trials may then require a large initial enrollment, with ongoing monitoring of both serologic and clinical endpoints. A major challenge leading to a degree of complexity in developing clinical trial protocols for serological endpoints is the lack of precise knowledge of incidence rates (9). A critical requirement for such a multi-trial strategy is the establishment of independent laboratories with similar or identical validated serologic assays to provide a harmonizing bridge between multiple vaccine products and multiple vaccine efficacy trials. The use of these laboratories for each clinical trial, or the sharing of critical specimens from a trial, should be required. Parameters that would distinguish the immune response resulting from vaccination versus from infection are under intense investigation, and there is an immediate need to develop assays to address this issue.
Efficacy trials need to be evaluated for both benefit and harm. The likelihood of SARS-CoV-2 reexposure is much higher than that of SARS-CoV-1, which has disappeared from community circulation, and hence longer-term evaluation of potential enhancement with reexposure is needed. This requirement does not preclude licensure based on the endpoints outlined above; however, it does indicate that more prolonged follow-up of the initial vaccine cohorts should be undertaken. The durability of clinical and serologic endpoints will also need to be explored, as waning of immunity is common with human coronavirus infections (10). Coronaviruses have a single-stranded RNA genome with a relatively high mutation rate. Although there has been some genetic drift during the evolution of the SARS-CoV-2 epidemic, major alterations in the spike protein are not extensive to date, especially in the regions thought to be important for neutralization; this enables cautious optimism that vaccines designed now will be effective against circulating strains 6 to 12 months in the future (11).
The possibility of performing controlled human challenge trials, in which a small number of volunteers are vaccinated and subsequently challenged with SARS-CoV-2, has been suggested. Such experiments, if designed to define potential immune correlates or winnow out less effective vaccine approaches, may have utility. However, this approach has shortcomings with respect to pathophysiology and safety (12). Although the risk of severe disease or death in young healthy individuals from COVID-19 is quite low, it is not zero, and we do not yet have proven effective therapies for COVID-19 to rescue volunteers with complications from such a challenge. It is likely that a SARS-CoV-2 challenge strain will, by design, cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients. Moreover, partial efficacy in young healthy adults does not predict similar effectiveness among older adults with major cofactors associated with COVID-19 disease, nor would it prove reduction of transmissibility to major susceptibility groups. Whether such experiments may be worthy of pursuit or would have a beneficial impact on timelines for vaccine development needs careful evaluation by an independent panel of ethicists, clinical trialists, and experts on vaccine development.
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https://science.sciencemag.org/content/368/6494/948

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