COVID-19 Variants: Vaccines, Diagnostics, and Therapeutics

COVID-19 Variants: Vaccines, Diagnostics, and Therapeutics

Updated October 29, 2021
COVID-19 Variants: Vaccines, Diagnostics, and Therapeutics
Introduction
Tracking and Studying Variants
As SARS-CoV-2, the virus that causes COVID-19, has
Identifying, tracking, and studying virus variants primarily
spread widely over time, a number of new variants have
relies on two public health functions: (1) genomic
been identified globally. According to the Centers for
surveillance, based on sequencing, and (2) genomic
Disease Control and Prevention (CDC), “a new virus
epidemiology, which studies the health effects associated
variant has one or more mutations that differentiate it from
with different variants. Increasing SARS-CoV-2 genomic
the wild-type or predominant virus variants already
sequencing to facilitate surveillance in the United States has
circulating among the general population.” Genetic
posed a challenge. Though genomic sequencing capacity
variation in circulating viruses is expected, especially with
exists in the academic and private laboratory sector, these
RNA viruses like SARS-CoV-2, which have high rates of
sectors have not been well connected to the public health or
mutation generally. When a virus infects its host, it uses the
health care sectors to readily enable large-scale and
host cell machinery to replicate itself. This replication
coordinated laboratory sample and data sharing for a
process is error prone and offers chances to introduce
nationwide virus sequencing effort. CDC has funded efforts
changes to the virus’s genetic code. Many of these changes
and partnerships to increase genomic sequencing and
are inconsequential, but a few improve the fitness of the
surveillance since fall 2020, including through collecting
virus, providing a selective advantage and establishing new
specimens for sequencing, and by partnering with
strains of the virus, which would be expected to increase in
academic, commercial, and public health laboratories. CDC
prevalence over time. Although they may occur in any part
has also awarded grants to state, local, territorial, and tribal
of the viral genome, changes in the genetic code for the
(SLTT) public health agencies to increase their capacity for
virus part that locks onto the host cell, known as the “spike
genomic surveillance. Genome sequences collected through
protein,” have been noted in certain SARS-CoV-2 variants.
surveillance and other sequencing efforts are shared to
These changes appear to strengthen viral attachment to the
public repositories, such as GenBank or GISAID (global
host cell, which can result in more efficient viral
initiative on sharing avian influenza data). These efforts
transmission (increased infectiousness). This type of change
have boosted U.S. SARS-CoV-2 sequencing by CDC and
does not have to correlate with a change in the clinical
SLTT labs from about 3,000 sequences per week in early
severity of infection (virulence), although it may.
2021 to a range of 40,000-90,000 sequences per week in
September and October.
Currently, the Delta variant is the predominant variant
strain circulating in the United States, according to CDC
Boosting genomic epidemiology poses another challenge.
data. Federal agencies are actively monitoring other
Genomic epidemiology can answer questions such as
variants of possible concern. Certain variants, both existing
whether certain variants are associated with more severe
and potential, may pose possible challenges to the
health outcomes or reduced effectiveness of medical
effectiveness of existing countermeasures—vaccines,
countermeasures, and enable the use of genomic data in
diagnostics, and therapeutics—and the development of new
outbreak response. Such efforts involve linking genomic
ones. Efforts have increased nationally to track the
surveillance data with other types of health data, such as on
emergence and spread of new variants, primarily through
patient characteristics, outcomes, or vaccination status. In
increasing genomic and other surveillance.
the United States, siloed health data systems, as well as
other legal and institutional barriers, inhibit the data
Given these concerns, Congress, in the American Rescue
integration that would enable more robust and real-time
Plan Act of 2021 (ARPA; P.L. 117-2) appropriated $1.75
genomic epidemiology. In addition, SLTT public health
billion to CDC specifically for SARS-CoV-2 genomic
agencies have varying capacity for genomic surveillance
sequencing and surveillance; other funding in the bill, such
and epidemiology for a number of reasons, including a lack
as for data modernization and forecasting, may also aid
of technology and trained personnel with bioinformatics
with variant tracking, as well as with coordination of such
expertise, among others. This sector is also already strained
efforts at the federal level. CDC has also used
by other aspects of the COVID-19 response. The Biden
appropriations from several prior coronavirus supplemental
Administration has allocated the ARPA genomic
appropriations acts to expand such efforts. P.L. 117-2
surveillance funds in an effort to address these issues: $1
further provided funding to the Food and Drug
billion for CDC and SLTT health agencies to expand
Administration (FDA) to support, among other things, the
sequencing, $400 million for new Centers of Excellence in
continued evaluation of COVID-19 countermeasures,
Genomic Epidemiology, and $300 million for a National
including with respect to emerging variants.
Bioinformatics Infrastructure. Even with new funding, it
may take time to build the infrastructure for robust
nationwide genomic surveillance and epidemiology, and
some legal and institutional barriers may remain.
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COVID-19 Variants: Vaccines, Diagnostics, and Therapeutics
Variants and Vaccines
sequence repositories, to identify potential viral mutations
The vaccines available thus far are designed to elicit a
or variants of concern. Test components are routinely
protective immune response to the SARS-CoV-2 spike
compared against these mutations to determine the effect, if
protein. SARS-CoV-2 variants with mutations in the spike
any, on test performance. FDA released a safety alert for
protein raise concerns that available vaccines may provide
clinical laboratory staff and health care providers in early
reduced protection. Data indicate that vaccines continue to
January 2021 based on this work to alert the community
provide strong protection against severe COVID-19 and
about potential impacts of variants on specific EUA tests.
death in the United States, including against currently
The agency has continued to provide updates on affected
circulating variants. To ensure that vaccines continue to
tests to the diagnostics community since this time.
provide robust protection against COVID-19, including
against emerging variants, FDA has authorized, and CDC
In September 2021, FDA issued notice of revisions to the
has endorsed, booster doses of the available vaccines,
EUAs of certain molecular, antigen, and serological tests,
including heterologous boosters (i.e., a mix-and-match
adding new conditions of authorization that must be met by
approach). As new variants emerge, vaccine dosing
test developers to account for new and emerging variants.
recommendations may be modified further.
Specifically, the conditions include updated labelling
requirements to clarify that a test’s performance is
Any changes to the currently approved or authorized
reflective of the variants circulating at the time of its
vaccines or vaccine regimens must be reviewed and
clinical evaluation. In addition, developers must “evaluate
approved by FDA, as explained in the Emergency Use
the impact of SARS-CoV-2 viral mutations on your
Authorization [EUA] for Vaccines to Prevent COVID-19
product’s performance” on an ongoing basis.
guidance. FDA does not expect vaccine developers to
conduct the same large clinical trials that were required for
Variants and Therapeutics
initial EUA issuance. Instead, the effectiveness of a
Several therapeutics are available for the treatment of
modified COVID-19 vaccine may be demonstrated through
COVID-19, and they differ with respect to their intended
immunogenicity studies comparing the immune response
use (e.g., treatment of mild to moderate or severe disease)
induced by the modified vaccine against the SARS-CoV-2
and mechanism of action (e.g., whether they target the virus
variant(s) with the immune response induced by the EUA-
itself or the body’s inflammatory response). For example,
authorized vaccine against the SARS-CoV-2 virus upon
FDA has granted EUA to several monoclonal antibody
which the vaccine was originally based. FDA guidance
(mAb) products, which are intended for the treatment of
provides recommendations for conducting studies assessing
mild to moderate COVID-19 in patients who are at high
the effectiveness of a modified COVID-19 vaccine as part
risk for progressing to severe disease.
of the primary vaccine series and as a booster dose.
The emergence of SARS-CoV-2 variants has raised concern
Variants and Diagnostics
about the effectiveness of existing therapeutics, particularly
The performance of COVID-19 tests, including molecular,
mAb products, which are designed to bind to the spike
antigen, and serology tests, may be affected by the
protein that allows the virus to infect the host cell in order
emergence of new variants. FDA released guidance in
to stop infection. In April 2021, FDA revoked the EUA for
February 2021—Policy for Evaluating Impact of Viral
the mAb bamlanivimab, citing a “sustained increase of
Mutations on COVID-19 Tests—to provide test developers
SARS-CoV-2 viral variants that are resistant to [it] alone
with recommendations for monitoring the impact of
resulting in the increased risk for treatment failure.” The
variants on their tests’ performance and considerations for
EUAs for other mAb products remain in effect (e.g.,
test design that can mitigate the impact of variants.
bamlanivimab and etesevimab, when administered
Molecular tests, such as polymerase chain reaction (PCR)
together). FDA has further modified EUAs for authorized
tests, identify the virus by detecting specific pieces of the
mAb products to require as a condition of authorization
viral genome, and have generally been developed using the
that, among other things, sponsors establish a process for
same reference sequence. If a test’s viral targets are altered
monitoring genomic databases for the emergence of global
in a variant, then the diagnostic may not detect them,
variants of SARS-CoV-2 and, if requested by FDA, provide
generating a false negative result. This performance issue
an assessment of the authorized products’ activity against
may be mitigated through the use of multiple targets in a
“any global SARS-CoV-2 variant(s) of interest.” Notably,
molecular test; most EUA-authorized PCR tests do have
the conditions of authorization for one mAb product
multiple targets, often in different parts of the viral genome.
(bamlanivimab and etesevimab) limit its use to those states,
Separately, antigen and serology test performance may be
territories, and U.S. jurisdictions in which the combined
affected if a viral genetic mutation affects the eventual
frequency of variants resistant to it is 5% or less, as
structure of viral proteins (e.g., antigens) that are targeted
determined by FDA based on CDC data. FDA has provided
by, or used as components in, these tests. These changes
recommendations for design of mAb development
may also lead to false negative results.
programs and considerations for emerging variants in
guidance (Development of Monoclonal Antibody Products
FDA has been “routinely monitoring publicly available
Targeting SARS-CoV-2, Including Addressing the Impact of
databases and has coordinated efforts to evaluate the impact
Emerging Variants, During the COVID-19 Public Health
of new virus variants on tests that have received … EUA.”
Emergency).
FDA used reports in the peer-reviewed literature on variants
of clinical significance, as well as identification of
Amanda K. Sarata, Specialist in Health Policy
mutations appearing with increasing frequency in public
Agata Bodie, Analyst in Health Policy
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COVID-19 Variants: Vaccines, Diagnostics, and Therapeutics

IF11789
Kavya Sekar, Analyst in Health Policy

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