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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.
[MORE]https://science.sciencemag.org/content/368/6494/948
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