Burk Declaration
- Date
- 2021-12-17
Summary
Document 40-16 in Case 2:21-cv-00702-CLM in the U.S. District Court, N.D. of Alabama, filed December 17, 2021 and labeled Burk Declaration Exhibit 16. It reproduces an FDA CBER review memorandum dated August 12, 2021 on Moderna's request to amend EUA 27073 for its COVID-19 vaccine. The memorandum assesses a third dose (0.5 ml) given at least 28 days after the second dose to individuals 18 years and older who have undergone solid organ transplantation or have an equivalent level of immunocompromise. It reviews two published studies and recommends amending the authorization, stating the known and potential benefits outweigh the known and potential risks for that group.
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Case 2:21-cv-00702-CLM Document 40-16 Filed 12/17/21 Page 1 of 4 FILED
2021 Dec-17 PM 01:27
U.S. DISTRICT COURT
N.D. OF ALABAMA
Burk Declaration
Exhibit 16
Case 2:21-cv-00702-CLM Document 40-16 Filed 12/17/21 Page 2 of 4
Review Memorandum
Date: August 12, 2021
To: The File
From: David Cho, PhD (CBER/OD)
Through: Peter Marks, MD, PhD (CBER/OD)
Applicant name: Moderna
Application Number: EUA 27073
Product: Moderna COVID-19 Vaccine
Subject: CBER Assessment of third dose of Moderna COVID-19 Vaccine
(0.5 ml) administered at least 28 days following the first two doses
of this vaccine to individuals who have undergone solid organ
transplantation, or who are diagnosed with conditions that are
considered to have an equivalent level of immunocompromise
This memorandum provides a summary, review, and recommendation on the submission by Moderna to
amend the emergency use authorization (EUA) of their COVID-19 vaccine to authorize administration of a
third dose of the vaccine to certain immunocompromised individuals age 18 years of age or older who have
received two doses of the Moderna COVID-19 vaccine and who have undergone solid organ
transplantation, or who are diagnosed with conditions that are considered to have an equivalent level of
immunocompromise.
Executive Summary
Moderna has provided a proposed Amendment to EUA 27073 to amend the emergency use authorization
(EUA) to include a third dose of the Moderna COVID-19 vaccine for certain immunocompromised
individuals. Reference is made to the EUA for Moderna COVID-19 Vaccine issued on December 18,
2020, which describes the safety and effectiveness of this vaccine based on a large placebo-controlled
randomized trial. Moderna’s current authorized indication is for active immunization to prevent
coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) in individuals age 18 years and older. The proposed additional indication for this submission is:
Individuals at least 18 years of age who have received two doses of the Moderna COVID-19 vaccine and
who have undergone solid organ transplantation, or who are diagnosed with conditions that are considered
to have an equivalent level of immunocompromise, may receive a third dose of the Moderna COVID-19
Case 2:21-cv-00702-CLM Document 40-16 Filed 12/17/21 Page 3 of 4
vaccine (0.5 ml) administered at least 28 days following the second dose of the two dose regimen of this
vaccine.
Review
The data presented in the EUA amendment are based on published literature (Hall VG, Ferreira VH, Ku T,
et al. (2021), A Randomized Trial of Third Dose mRNA-1273 Vaccine in Transplant Recipients. NEJM
DOI: 10.1056/NEJMc2111462) reporting that the standard two dose vaccination with mRNA-based
COVID vaccines may produce suboptimal immunogenicity in organ transplant patients and the use of a
third dose in these patients as well as those that are considered to have an equivalent level of
immunocompromise could improve the immunological response in these patients without a significant
change in the safety profile. The paper describes a double-blind, randomized-controlled study conducted in
120 individuals who had undergone various solid organ transplant procedures (heart, kidney, kidney-
pancreas, liver, lung, pancreas) a median of 3.57 years earlier (range 1.99-6.75 years). A third dose of the
Moderna COVID-19 vaccine was administered to 60 individuals approximately 2 months after they had
received a second dose (i.e., doses at 0, 1 and 3 months); saline placebo was given to 60 individuals or
comparison. The primary outcome was anti-RBD antibody at 4 months greater than 100 U/mL. This titer
was selected based on NHP challenge studies as well as a large clinical cohort study and indicated to the
investigators that this antibody titer was possibly protective. Secondary outcomes were based on a virus
neutralization assay and polyfunctional T cell responses. Baseline characteristics were comparable
between the two study arms as were pre-intervention anti-RBD titer and neutralizing antibodies. Levels of
SARS-CoV-2 antibodies occurred four weeks after the third dose in 33/60 (55.0%) of the Moderna
COVID-19 vaccinated group and 10/57 (17.5%) of the placebo individuals. In the 60 individuals who
received a third vaccine dose, the adverse event profile was similar to that after the second dose and no
grade 3 or grade 4 adverse events were reported.
CBER also reviewed a supportive and confirmatory paper using a similar mRNA COVID vaccine (Pfizer-
BioNTech COVID-19 vaccine) by Kamar et al. (2021; Three Doses of an mRNA Covid-19 Vaccine in
Solid-Organ Transplant Recipients. NEJM, DOI: 10.1056/NEJMc2108861), which describes a single arm
study conducted in 101 individuals who had undergone various solid organ transplant procedures (heart,
heart, kidney, liver, lung, pancreas) a median of 97+8 months previously and received the standard two
doses of the Pfizer-BioNTech COVID-19 Vaccine (similar COVID-19 vaccine using mRNA). A third dose
of Pfizer-BioNTech COVID-19 vaccine was administered to 99 of these individuals approximately 2
months after they received a second dose. Levels of SARS-CoV-2 antibodies meeting the pre-identified
criteria for success occurred four weeks after the third dose of the Pfizer-BioNTech COVID-19 vaccine in
26/59 (44.0%) of those who were initially considered to be seronegative; 67/99 (68%) of the entire group
receiving a third had an increase in antibody titers that the investigators considered significant. In those
who received a third vaccine dose, the adverse event profile was similar to that after the second dose, and
no grade 3 or grade 4 events were reported.
Recommendation
FDA has been continuously reviewing the literature for information on the safety and efficacy of vaccines
to prevent COVID-19 in the immunocompromised. Based on the data in the Hall et. al manuscript, the
administration of a third dose of the Moderna COVID-19 vaccine appears to be only moderately effective
Case 2:21-cv-00702-CLM Document 40-16 Filed 12/17/21 Page 4 of 4
in increasing antibody titers in the individuals studied. It is also unclear whether the antibodies generated
from the third dose are protective and durable. Since the third dose of vaccine could lead to a false sense of
protection, individuals who receive the third dose should continue barrier measures and the close contacts
of immunocompromised persons should be vaccinated as appropriate for their health status. There were no
serious adverse events reported in the Hall et. al publication. Despite the moderate enhancement in
antibody titers, the totality of data (including the supportive paper by Kamar et al. and demonstrated
efficacy of the product in the elderly and persons with co-morbidities) supports the conclusion that a third
dose of the Moderna COVID-19 vaccine may be effective in this population, and that the known and
potential benefit of a third dose of Moderna COVID-19 vaccine outweigh the known and potential risks of
the vaccine for immunocompromised individuals at least 18 years of age who have received two doses of
the Moderna COVID-19 vaccine and who have undergone solid organ transplantation, or who are
diagnosed with conditions that are considered to have an equivalent level of immunocompromise.
Regarding “the equivalent level of immunocompromise” statement, FDA recognizes that there are a myriad
of different immunocompromising conditions. Solid organ transplant patients are immunosuppressed
because they are taking a variety of immunosuppressive medications such as cyclosporin, tacrolimus,
sirolimus, mycophenolate, azathioprine, and anti-thymocyte globulin. These immunosuppressive
medications are used in a variety of other conditions to address immune dysregulation. The effects of these
drugs in these other conditions are very similar to the effects in those who have undergone solid organ
transplantation: that is there is interference with the cellular and humoral immune response. Thus,
individuals receiving these medications whether in the setting for solid organ transplant or for the treatment
of immune dysregulation likely both have a similarly attenuated response to the administration of vaccines
to prevent COVID-19. Conversely, it is reasonable to extrapolate that the administration of an additional
dose of a COVID-19 vaccine to these individuals with immune dysregulation may produce similar
responses to those seen in solid organ transplant. It is also reasonable to make the extrapolation that
individuals with inherited or acquired conditions that produce reduction in the cellular or humoral immune
response similar to that seen in solid organ transplant may produce similar immune responses to a third
dose of a COVID-19 vaccine. We therefore believe it is appropriate to amend the authorization to include a
third dose of the vaccine for individuals at least 18 years of age who are diagnosed with conditions that are
considered to have an equivalent level of immunocompromise.
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