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A strategic approach to COVID-19 vaccine R&D

ILLUSTRATION: DAVIDE BONAZZI/SALZMANARTThere 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 EndpointsThe 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 diseas
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