key: cord-0821043-rgj8vs9z
authors: Plotkin, Stanley A
title: Vaccination Against Severe Acute Respiratory Syndrome Coronavirus 2
date: 2020-08-03
journal: J Pediatric Infect Dis Soc
DOI: 10.1093/jpids/piaa093
sha: d44cff1bf28bd90ac5de20882485f0d42d539399
doc_id: 821043
cord_uid: rgj8vs9z

Over 100 attempts are being made to develop a vaccine for use in the epidemic of COVID-19. Many different technologies are being used in an effort to prevent the infection or at least the disease.

There is a universal and widely acknowledged need for a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because of its widespread circulation and high mortality and morbidity. Although children usually have mild disease, that is not always the case and, additionally, children may act as a reservoir for the virus. Although much is not known about the mechanisms of disease causation, the need for a preventive vaccine is beyond question, as the virus has brought societies to a halt as no other microbe has done since the 1918-1919 H1N1 pandemic influenza strain.

Fortunately, the reaction of vaccinologists has been phenomenal. I have more than 60 years of experience in the field, and I have never seen a vaccine effort involve as many candidates as the current efforts to develop and license a vaccine against this new coronavirus. As discussed below, there are many potential impediments to development of a vaccine against SARS-CoV-2, but prior experience with SARS-1 and Middle East respiratory syndrome coronaviruses suggest that vaccine development is feasible, despite many potential pitfalls [1, 2] .

The basic construction of the SARS-CoV-2 virus is understood. On the surface of the virus are 2 proteins: the spike protein (S) and the membrane protein (M). Within the virus particle is the nuclear protein (N). Although some vaccine efforts use the whole inactivated or attenuated virus, the great majority concentrate on the Spike protein, which contains 2 parts: S1 and S2. The S1 portion contains an epitope called the receptor binding domain (RBD), which is responsible for attachment of the virus to the angiotensin-converting enzyme 2 receptor on cells in the respiratory tract and elsewhere in the body. The S2 portion fuses with the membrane of the cell, permitting the attached virus to enter the cell. Neutralizing antibodies are directed against the RBD [3] . Table 1 summarizes the current approaches to development of vaccines against SARS-CoV-2. The table is incomplete but lists the most advanced and prominent candidates. Vaccine developers have experimented with many different ways to present the S protein or, in some cases, the RBD domain to the immune system. Some simply use the adjuvanted S protein as the vaccine, but many more use live or nonreplicating viruses as vectors to present the S protein to the vaccinee. Foremost among these vectors at the moment are human and chimpanzee adenoviruses or attenuated vaccinia virus. However, multiple other vectors are being tried [4, 5] .

In addition, in line with the invention of new vaccine technologies, nucleic acid approaches are prominent in the race to develop a SARS-CoV-2 vaccine. Plasmid DNA coding for the spike and delivered intradermally via electroporation is being tested as a vaccine. The more recent messenger RNA technologies are in trial to deliver genetic information for the S protein, either as lipidated RNA or self-amplified RNA.

In total, more than 100 SARS-CoV-2 vaccine candidates have been announced, but it is likely that most projects will not leave the drawing board. However, it is likely that the majority will reach clinical trials. Indeed, a number of projects are already in clinical trials. It is difficult to characterize their status as developers are attempting to compress phase 1, 2, and 3 trials in an effort to arrive at an endpoint quickly, and few results have been published. However, for this observer, the vaccine candidates in the lead are DNA plasmids, messenger RNA, inactivated virus, chimpanzee adenovirus vector, and human adenovirus vector. The changing epidemiology of coronavirus 2019 is forcing developers to change the location of their trials, with many seeking venues in Latin America and India.

There are many important issues that must be answered in these trials, including: Can vaccination prevent infection as well as disease? Can vaccines give long-lasting or only temporary immunity? What are the immunologic correlates of protection? Will neutralizing antibodies suffice, or are T-cell responses necessary? Will vaccines generate enhancing as well as protective immune responses? Will evolution of the SARS-CoV-2 virus require changes in vaccine antigens? Some of these questions will be difficult to answer in typical phase 3 trials, and some observers, including myself, have raised the possibility of challenging young, healthy volunteers to obtain those answers [6] . That proposition is currently being evaluated [7] .

The coming weeks and months will bring answers to these and other questions. Unfortunately, vaccine development is a long and difficult process, and unexpected findings are to be expected.

Potential conflicts of interest. S. A. P. is a consultant to many companies working on vaccines against SARS-2-Cov. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Inactivated SARS-CoV vaccine elicits high titers of spike protein-specific antibodies that block receptor binding and virus entry

Middle East respiratory syndrome and severe acute respiratory syndrome

Rational vaccine design in the time of COVID-19

The challenges of vaccine development against a new virus during a pandemic

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

Extraordinary diseases require extraordinary solutions

WHO Advisory Group Tasked to Consider the Feasibility, Potential Value, and Limitations of Establishing a Closely Monitored Challenge Model of Experimental COVID-19 Infection and Illness in Healthy Young Adult Volunteers. World Health Organization Advisory Group