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On December 18, 2020, the Food and Drug Administration (FDA) issued an Emergency Use

Authorization (EUA) for the Moderna COVID-19 (mRNA-1273) vaccine (ModernaTX, Inc;
Cambridge, Massachusetts), a lipid nanoparticle-encapsulated, nucleoside-modified mRNA
vaccine encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2, the virus that
causes coronavirus disease 2019 (COVID-19) (1). This vaccine is the second COVID-19 vaccine
authorized under an EUA for the prevention of COVID-19 in the United States (2). Vaccination
with the Moderna COVID-19 vaccine consists of 2 doses (100 μg, 0.5 mL each) administered
intramuscularly, 1 month (4 weeks) apart. On December 19, 2020, the Advisory Committee on
Immunization Practices (ACIP) issued an interim recommendation* for use of the Moderna
COVID-19 vaccine in persons aged ≥18 years for the prevention of COVID-19. To guide its
deliberations regarding the vaccine, ACIP employed the Evidence to Recommendation (EtR)
Framework,† using the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) approach.§ Use of all COVID-19 vaccines authorized under an EUA, including the
Moderna COVID-19 vaccine, should be implemented in conjunction with ACIP’s interim
recommendations for allocating initial supplies of COVID-19 vaccines (3). The ACIP
recommendation for the use of the Moderna COVID-19 vaccine under EUA is interim and will be
updated as additional information becomes available.

Since June 2020, ACIP has convened 10 public meetings to review data on the epidemiology of
COVID-19 and the potential use of COVID-19 vaccines, including the Moderna COVID-19 vaccine
(4). Within the EtR Framework, ACIP considered the importance of the public health problem of
COVID-19, as well as resource use, benefits and harms, patients’ values and preferences,
acceptability, feasibility, and equity for the Moderna COVID-19 vaccine. To inform the EtR
Framework, the COVID-19 Vaccines Work Group, comprising experts in infectious diseases,
vaccinology, vaccine safety, public health, and ethics, held 28 meetings to review COVID-19
surveillance data, evidence for vaccine efficacy and safety, and implementation considerations
for COVID-19 vaccines, including the Moderna COVID-19 vaccine. After a systematic review of
available data, the Work Group used the GRADE approach to assess the certainty of evidence
for outcomes related to the vaccine, rated on a scale of 1 (high certainty) to 4 (very low
certainty) (5). Work Group conclusions regarding certainty of evidence for the Moderna COVID-
19 vaccine were presented to ACIP at public meetings.

The body of evidence for the Moderna COVID-19 vaccine was primarily informed by one large,
randomized, double-blind, placebo-controlled Phase III clinical trial that enrolled approximately
30,000 participants aged 18–95 years (median = 52 years) (6–9). Interim findings from this
clinical trial, using data from participants with a median of 2 months of follow-up, indicate that
the Moderna COVID-19 vaccine efficacy after 2 doses was 94.1% (95% confidence interval =
89.3%–96.8%) in preventing symptomatic, laboratory-confirmed COVID-19 among persons
without evidence of previous SARS-CoV-2 infection, which was the primary study endpoint.
High efficacy (≥86%) was observed across age, sex, race, and ethnicity categories and among
persons with underlying medical conditions. Ten hospitalizations due to COVID-19 were
documented; nine in the placebo group and one in the vaccine group (9). Preliminary data
suggest that the Moderna COVID-19 vaccine might also provide some protection against
asymptomatic SARS-CoV-2 infection (7). Among vaccine recipients, reactogenicity symptoms,
defined as solicited local injection site or systemic adverse reactions during the 7 days after
vaccination, were frequent but mostly mild to moderate. Systemic adverse reactions were more
commonly reported after the second dose than after the first dose and were more frequent and
severe in persons aged 18–64 years than in those aged ≥65 years. Most local and systemic
adverse reactions occurred within the first 1–2 days after vaccine receipt and resolved in a
median of 2–3 days. Severe local or systemic adverse reactions (grade ≥3 reactions¶) occurred
more commonly in vaccine recipients than in placebo recipients (21.6% versus 4.4%). Among
vaccine recipients, 9.1% reported a grade ≥3 local injection site reaction, and 16.5% reported a
grade ≥3 systemic adverse reaction. The frequency of serious adverse events** observed was
low in both the vaccine (1.0%) and placebo (1.0%) recipients and without meaningful
imbalances for specific serious adverse events between the two groups (8). No specific safety
concerns were identified in subgroup analyses by age, race, ethnicity, underlying medical
conditions, or previous SARS-CoV-2 infection. A detailed summary of safety data, including
information on reactogenicity, is available at https://www.cdc.gov/vaccines/covid-19/info-by-
product/moderna/reactogenicity.html.

From the GRADE evidence assessment, the level of certainty for the benefits of the Moderna
COVID-19 vaccine was type 1 (high certainty) for the prevention of symptomatic COVID-19.
Evidence was type 2 (moderate certainty) for the estimate of prevention of COVID-19–
associated hospitalization and type 4 (very low certainty) for the estimates of prevention of
asymptomatic SARS-CoV-2 infection and all-cause death. Data on COVID-19–associated
hospitalizations and deaths are limited at this time; however, a vaccine that effectively prevents
symptomatic infection is expected to also prevent associated hospitalizations and deaths.
Regarding certainty of evidence related to possible harms after vaccination, evidence was type
2 (moderate certainty) for the estimate of serious adverse events and type 1 (high certainty) for
the estimate of reactogenicity. Data reviewed within the EtR Framework supported the use of
the Moderna COVID-19 vaccine. ACIP determined that COVID-19 is a major public health
problem and that use of the Moderna COVID-19 vaccine is a reasonable and efficient allocation
of resources. Whereas there might be uncertainty about how all populations value the vaccine,
it was determined that for most populations, the desirable effects outweigh the undesirable
effects, making the vaccine acceptable to implementation stakeholders. In addition,
implementation of administration of the Moderna COVID-19 vaccine is feasible. Although the
vaccine requires a freezer (–20oC [–4oF]) for long-term storage, it is stable at refrigerator
temperatures (2–8oC [35–46oF]) for up to 30 days after thawing. This characteristic will
facilitate feasibility of administration of the Moderna COVID-19 vaccine in most community
settings, once supply allows. Advancing health equity, however, will require efforts to identify
and reduce access-related barriers to vaccination, as well as engagement with community
organizations and leaders among groups who experience disproportionate COVID-19–related
morbidity and mortality, and to expand access to clear and accurate information on COVID-19
vaccines (10). The GRADE evidence profile and supporting evidence for the EtR Framework are
available at https://www.cdc.gov/vaccines/acip/recs/grade/covid-19-moderna-vaccine.html
and https://www.cdc.gov/vaccines/acip/recs/grade/covid-19-moderna-etr.html.

Before vaccination, the EUA Fact Sheet (11) should be provided to recipients and caregivers.
Providers should counsel Moderna COVID-19 vaccine recipients about expected local and
systemic reactogenicity. The Moderna COVID-19 vaccine is not interchangeable with other
COVID-19 vaccine products; the safety and efficacy of a mixed-product series have not been
evaluated. ACIP does not state a product preference; a person may receive any recommended
COVID-19 vaccine series. However, persons should complete the series with the same COVID-19
product they received for the first dose. Additional clinical considerations, including details of
administration and use in special populations (e.g., persons who are pregnant,
immunocompromised or who have a history of severe allergic reactions) are available at
https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html. The
interim recommendation and clinical considerations are based on use of the Moderna COVID-
19 vaccine under an EUA and might change as more evidence becomes available. ACIP will
continue to review additional data as they become available; updates to recommendations or
clinical considerations will be posted on the ACIP website (3).

Literature review
Here are some of the key questions that scientists hope to answer to develop a coronavirus
vaccine.
Do people develop immunity?
Vaccines help a person to generate an immune response against an infection without first being
exposed to the pathogen. Studies of other coronaviruses, such as the four that cause some
common colds, lead most researchers to assume that people who have recovered from SARS-
CoV-2 infection will be protected from reinfection for a period of time. But that assumption
needs to be backed by evidence, says Michael Diamond, a viral immunologist at Washington
University in St. Louis, Missouri. “We don’t know that much about immunity to this virus.”

A preprint1 posted online on 14 March by a team based in China looked at two rhesus
macaques (Macaca mulatta) that had recovered from SARS-CoV-2 infection, which caused them
only mild illness. The monkeys did not seem to become re-infected when researchers exposed
them to the virus for a second time four weeks after their initial exposure. Researchers will be
looking for evidence that humans react in the same way, for instance by studying people
potentially exposed multiple times, Diamond says.

If humans do develop immunity, how long does it last?


That’s another big unknown. Immunity is short-lived for the coronaviruses that cause common
colds; even people who have high levels of antibodies against these viruses can still become
infected, says Stanley Perlman, a coronavirologist at the University of Iowa in Iowa City.

The evidence is more equivocal for the two other coronaviruses that have triggered epidemics:
those that cause severe acute respiratory syndrome (SARS) and Middle East respiratory
syndrome (MERS). Perlman says his team has found that after people recover from MERS, their
antibodies against the virus drop precipitously. He also says that his team has gathered data —
not yet published — showing that SARS antibodies are still present in the body 15 years after
infection. But it’s not clear whether this immune response is enough to prevent reinfection.
“We don’t have good evidence of long-lasting immunity, but we also don’t have really good
data from both SARS and MERS,” Perlman adds.

What kind of immune response should vaccine developers look for?


The phase I trial that began this week focuses on the safety of a vaccine developed by Moderna,
a company based in Cambridge, Massachusetts. But researchers will also look closely at the
nature of the immune response the vaccine summons.

The Moderna vaccine consists of an RNA molecule. Like many of the other SARS-CoV-2 vaccines
in development, it is designed to train the immune system to make antibodies that recognize
and block the spike protein that the virus uses to enter human cells.

“I think it’s reasonable as a first pass, but we will learn that, perhaps, antibody responses to the
spike exclusively may not be the whole story,” says Diamond. A successful SARS-CoV-2 vaccine
might need to prompt the body to generate antibodies that block other viral proteins, for
instance, or make T cells that can recognize and kill infected cells.
How do we know if a vaccine is likely to work?
Normally, vaccines go into human trials after tests for safety and effectiveness in animals. But
the Moderna vaccine and another being developed by Inovio Pharmaceuticals in Plymouth
Meeting, Pennsylvania, are being tested in animals at the same time as human phase I trials are
happening. Inovio plans to begin its first human trial in April.

“In a non-emergency situation you might do this in a more serial way, but in this case a lot of
things are being done in parallel,” says Barney Graham, deputy-director of the US National
Institutes of Health (NIH) Vaccine Research Center in Bethesda, Maryland, which is sponsoring
the Moderna vaccine trial.

In a 2 March preprint2, researchers reported injecting Inovio’s vaccine — a DNA molecule


carrying instructions to make the spike protein — into mice and guinea pigs. They found that
the animals produced both antibodies and T cells against the virus. Study leader Kate Broderick,
Inovio’s senior vice-president for preclinical research and development, says that her team has
now given the vaccine to monkeys and is soon to start studies in which vaccinated animals are
infected with the virus to see whether they are protected. Such ‘challenge’ studies are also in
the works for the Moderna vaccine, says Graham.

He adds that large, costly trials of whether a vaccine can prevent infections in people won’t
proceed without such data from animals. Diamond expects that as researchers learn more
about the infection from both human and animal studies, they will get a better sense of which
vaccines are likely to work best. “It may not be the most efficient way to do it. But it may be the
most expedient way to generate a vaccine,” says Diamond.

Will it be safe?
Because they are given to large numbers of healthy people, vaccines usually have a higher bar
for safety than do drugs administered to people who are already ill. With SARS-CoV-2 vaccines,
researchers’ main safety concern is to avoid a phenomenon called disease enhancement, in
which vaccinated people who do get infected develop a more severe form of the disease than
people who have never been vaccinated. In studies of an experimental SARS vaccine reported3
in 2004, vaccinated ferrets developed damaging inflammation in their livers after being infected
with the virus.
Peter Hotez, a vaccine scientist at Baylor College of Medicine in Houston, Texas, thinks potential
vaccines should be tested in animals first to rule out disease enhancement, before trials move
on to humans. He says he understands the reasoning for pushing SARS-CoV-2 vaccines to
human tests quickly, but adds that, because of the possibility that a vaccine could enhance
disease, “I’m not sure this is the vaccine you want to do it for”.

In testing the Moderna vaccine, Graham says, the NIH will move to larger human studies only
once human and animal studies confirm that the vaccine is safe. He says the risk of
enhancement is low, but “the risk of not getting vaccines advanced quickly — so that we can
have something available for the next winter season to at least test in the field — that risk is
fairly high

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