How Can the Development of Coronavirus Vaccines Be Accelerated?

The nonclinical safety evaluation of new vaccine candidates is performed prior to and during the
conduct of clinical trials. Although the International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use has not issued guidelines for the nonclinical safety
evaluation of vaccines, several countries and the WHO have issued general guidance documents.37–39
These guidelines cover not only the types of nonclinical toxicology studies needed to support vaccine
clinical trials and licensing but also various important aspects of the study design such as species
selection, dose selection, dosing regimen, and type of end points assessed. Regulatory toxicology studies
for vaccines generally follow similar study design as small molecule and biotherapeutics, with additional
end points to assess acute phase response and immunogenicity of the vaccine antigens. Regulatory
guidelines and key aspects of regulatory toxicology studies (study design, study conduct, commonly
observed findings, and interpretation) for vaccines were reviewed in a recently published Society of
Toxicologic Pathology (STP) Scientific and Regulatory Policy Committee (SRPC) Points to Consider article
in Toxicologic Pathology and covered in an STP Continuing Education course in August 2020. For all new
prophylactic candidate vaccines, the general requirement for nonclinical safety assessment prior to the
initiation of phase 1 clinical trials includes one repeat-dose toxicity study in a single species with local
tolerance assessment and a recovery arm to assess the reversibility and to detect any delayed toxicity
due to a delayed immune response, and additional safety testing as appropriate to adequately
characterize risk. Nucleic acid–based vaccines (eg, attenuated viral vectors) may also require
biodistribution/persistence studies. Before enrolling pregnant women and women of childbearing
potential who are not actively avoiding pregnancy in clinical trials, DART studies are also needed. In
nonclinical toxicology studies with prophylactic vaccines, the full human dose should be administered
when feasible, and the number of doses administered is the same as or one more than the anticipated
number of clinical doses administered as a vaccination regimen over a year. The study duration (typically
2 or more weeks after the last dose) and interval between doses (typically 2-3 weeks but can be as short
as 1 week) are based on the onset and duration of the antibody response, and the dosing interval is
generally shorter than that in humans. There is precedent for using a case-by-case base approach to the
nonclinical toxicology testing paradigm for vaccines during public health emergencies such as the Ebola
outbreak. In 2018, the WHO released guidelines on the quality, safety, and efficacy of Ebola vaccines.
This guideline helped to define the nonclinical package that could safely support initiation of phase I
clinical trials in a public health emergency. Initiation of clinical trials without nonclinical data (but with
immunogenicity data) could be allowed if the vaccine is based on a platform technology for which there
is good nonclinical and clinical experience demonstrating safety. Experience gained in the development
of Ebola vaccines can be helpful to understand ways to accelerate the development of SARS-CoV-2
vaccine without compromising nonclinical safety testing. and preclinical efficacy data with the vaccine
candidate were used to accelerate phase 1 entry during the West African Ebola outbreak. Additional
nonclinical safety studies were performed in parallel with clinical development, using data available
from marketing applications. To address the COVID-19 public health emergency, the United States Food
and Drug Administration (FDA) has issued a guidance in June 2020 to assist sponsors in the clinical
development and licensure of vaccines for the prevention of COVID-19. This guidance reiterates that the
safety and efficacy of COVID-19 vaccines in clinical trials and subsequent licensing will have been subject
to the same expectations as vaccines not developed under emergency situations. As the FDA guidance
states.

The FDA guidance indicates that nonclinical safety studies will be required prior to proceeding to FIH
clinical trials for vaccine candidates that are truly novel product types without any existing nonclinical
and clinical data. However, if there is existing product safety information, nonclinical safety studies
would not be required before FIH. The guidance also specifically discusses the example of a vaccine
candidate made using a platform technology used for an already licensed vaccine or well-characterized
investigational vaccines and encourages leveraging the toxicology data from repeat-dose toxicity
studies, biodistribution studies and clinical data from the previously existing products to support FIH. A
platform technology is one that has standardized components which are consistent across target
vaccines, such that the only change is in the antigen or nucleic acid sequence for antigen expression. In
such cases, FDA asks vaccine manufacturers to summarize their aggregate nonclinical and clinical
findings observed with the previously existing products using the platform and to provide a rationale for
using the existing data in lieu of performing nonclinical safety studies. Further, for vaccine candidates
that are based on existing platforms, but for which changes have been made to target specific antigens,
additional, limited nonclinical studies assessing the immunogenicity and safety of the specific antigen
may be required and submitted in parallel with preliminary clinical trials. For novel platforms, based on
the FDA guidance, interim data (eg, in-life data tables) from ongoing toxicity studies and the submission
of draft unaudited toxicity study reports may be sufficient to support proceeding to phase 1 clinical
trials, as long as the final fully audited reports are available to FDA within 120 days of the start of the
phase 1 trial. The FDA urged the sponsors of COVID-19 vaccine candidates to engage in early
communications with FDA to discuss the type and extent of nonclinical testing required to support FIH
clinical trials and further clinical development.

Potential Safety Risks Associated With Coronavirus Vaccines

To date, enhanced disease has not been observed with SARSCoV-2 vaccines in preclinical models or
humans. However, vaccine-related enhanced disease was reported after some viral infections and
following vaccination against some viruses, including in animal models administered SARS-CoV-1 and
MERS vaccine candidates which appear to be due to Th2-type responses. This has raised concerns of a
potential theoretical risk with SARS-CoV-2 vaccines. Enhanced disease can be associated with
antibodydependent enhancement (ADE), which involves the binding of antibodies to the virus to form
an antibody/virus complex which enhances viral entry into macrophages and other immune cells. As
reviewed by Smatti and colleagues in 2018, this was originally reported in 1964 with a flavivirus although
it has been shown to occur with a wide variety of viruses since then. Viral pathogenesis is closely
interlinked with host’s immune response, and a better understanding of the virus–host dynamic is
important in the development of safe and efficacious vaccines. Viral infections are associated with
different types of antibodies including neutralizing, enhancing, non-neutralizing, and non-enhancing
antibodies. There are several viral factors that are important in enhanced disease such as viral type,
strain, and surface proteins which are the predominant contributors to antibody development. There
are also host factors of relevance, such as T and B cell responses, and specifically the antibody titer, type
and class, and the presence of complement. The host’s genetics may also be relevant, including
polymorphism in genes associated with innate and adaptive immune responses to viruses such as
cellular receptor genes including Fc gamma receptor (FcgR) and major histocompatibility complex
(MHC), as well as genes related to cytokine and complement pathways. Another mechanism by which
enhanced disease may occur after viral infection is associated with the development of a Th2-type
immune response, rather than the protective Th1 response needed to effectively eliminate the
pathogen. Previous vaccine development efforts (in the 1960s) with a formalin-inactivated vaccine for
respiratory syncytial virus (RSV) demonstrated the potential for vaccine-associated enhancement of
disease. RSVs–naive children were administered the formalin-inactivated whole virus vaccine candidate
(FI-RSV) and experienced vaccine-enhanced disease (characterized by an increased frequency of
infection and/or increased severity of respiratory disease) upon subsequent natural exposure to RSV,
with the death of 2 FI-RSV-vaccinated infants (following a natural infection at 16-18 months of age).RSV–
mediated disease enhancement was not observed in individuals previously infected with RSV, regardless
of subsequent immunization. Histomorphologic features in the lungs of humans included inflammatory
response (predominantly neutrophils and eosinophils) with evidence of immune complex formation and
complement activation.50 Subsequent research in animal models showed similar features in mice, and
the immune response was characterized as Th2 dominant, with a poorly neutralizing antibody response.
This was different from the ADE described for viruses with tropism for macrophages, such as the human
dengue virus (a flavivirus) and feline infectious peritonitis (FIP) virus in cats (a coronavirus).