This 42-day study prompted FDA to approve Moderna booster shots for immune compromised

This article goes into the nitty-gritty about the Emergency Aurhotization approval by the FDA for the booster shots for the immune-compromised.

The Joint Commission on Immunisation and Vaccination (JCVI) published on June 30, 2021, interim advice regarding COVID-19 booster shots for winter 2021 – 2022.

JCVI advises UK health departments on immunization. In their report,

The Joint Committee on Vaccination and Immunisation (JCVI) interim advice, based on existing evidence, is to offer COVID-19 booster vaccines to the most vulnerable, starting from September 2021. The booster programme will aim to provide additional resilience against variants, and maximise protection in those who are the most vulnerable to serious disease from COVID-19 ahead of the winter months, when there is increased pressure on the NHS as non-COVID-19 emergency demand is at its highest.

A booster dose would be offered to groups in 2 stages and, if possible, delivered alongside the annual influenza vaccination. In the first stage, a booster would be offered to:

adults aged 16 years and over who are immunosuppressed

those living in residential care homes for older adults

all adults aged 70 years or over

adults aged 16 years and over who are considered clinically extremely vulnerable

frontline health and social care workers

As soon as practicable after the first stage, the second stage would see a booster offered to:

all adults aged 50 years and over

adults aged 16 to 49 years who are in an influenza or COVID-19 at-risk group

adult household contacts of immunosuppressed individuals

This UK report is relevant to the US because the UK and US health agencies have parallel programs concerning health advisories.

If you look back at the list of people who will need the booster shot, the first group is the adults aged 16 years and over who are immunosuppressed.

So yesterday, the FDA granted EUA or Emergency Use Authorization for Moderna and Pfizer to give booster shots to guess who? The immune-compromised!

Quote from the EUA letter of the FDA to Pfizer,

On August 12, 2021, having concluded that revising this EUA is appropriate to protect the public health or safety under section 564(g)(2) of the Act, FDA again is reissuing the letter in its
entirety with revisions incorporated to authorize for emergency use a third dose of the PfizerBioNTech COVID-19 vaccine administered at least 28 days following the two dose regimen of this vaccine in individuals 12 years of age or older who have undergone solid organ transplantation, or individuals 12 years of age or older who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise.

Below is taken from the FDA letter to Moderna, granting EUA for a third shot,

For the August 12, 2021 authorization of a third dose of the Moderna COVID-19 vaccine in individuals 18 years of age or older who have undergone solid organ transplantation, or individuals 18 years of age or older who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise, FDA reviewed safety and effectiveness data reported in two manuscripts on solid organ transplant recipients.

Why are they recommending a booster shot for organ transplant patients?

The answer came from the authors of Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. It was published on August 11, 2021. Remember the date.

In organ-transplant recipients, the standard two-dose vaccination strategy for coronavirus disease 2019 (Covid-19) has suboptimal immunogenicity.

Meaning, the two previous two shots of Moderna didn’t work.

The middle of the abstract of Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients, published in the New England Journal of Medicine, said that the vaccine worked in the study group,

After the third dose, the median percent virus neutralization was 71% in the mRNA-1273 group and 13% in the placebo group (95% CI for the between-group difference, 11 to 76 percentage points), and the percentage of patients above the 30% threshold for neutralizing antibody positivity was 60% and 25%, respectively (relative risk, 2.4; 95% CI, 1.5 to 4.0)

The third shot boosted the antibody levels and the T-cell immune response too.

Median severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific T-cell counts were greater after the third dose in the mRNA-1273 group than in the placebo group (432 vs. 67 cells per 10⁶ CD4+ T cells; 95% CI for the between-group difference, 46 to 986).

There was a minimal polyfunctional CD8+ T-cell response in both groups.

Note that the placebo group are also producing antibodies and T-cells.

The duration of the study is short (42 days). In the supplement to their study, You can find the study duration at the bottom of page 2,

Patients were enrolled and vaccinated between May 25, 2021 to June 3, 2021. Patients were followed for outcomes till July 5, 2021.

That’s really short. The authors mentioned that as one of the limitations in their study,

This trial had short follow-up and was not powered to detect differences in clinical outcomes.

Clinical outcomes. The study did not cover how the study group will respond to real-life situations like

How long will the antibodies last?
Will they have effective immunity to coronavirus infections?
Will the antibodies that they develop turn into a hyperimmune response upon exposure to a future coronavirus infection?

The hyperimmune response or antibody-dependent enhancement (ADE) has been demonstrated many times in animal studies when attempts to make vaccines against the other coronaviruses like the SARS and the MERS were made.

The vaccinated animals developed an immune response against the vaccines, but when exposed to the wild-type coronavirus, they developed a hyperimmune response and died.

A reference for ADE is listed below.

Another quote from the Moderna study (emphasis is mine),

We also acknowledge that the cutoff value of 100 U per milliliter for the anti-RBD antibody level is arbitrary and is not necessarily predictive of resistance to infection.

I don’t think any interpretation of that quote is necessary.

NEJM Editorial

A quote from the Third Time’s a Charm — Covid-19 Vaccine Hope for Solid-Organ Transplant Recipients.

Together these results provide convincing evidence of enhanced vaccine efficacy in transplant recipients

The editors did have a question and comment.

But can one generalize from this small trial? There was some imbalance between the vaccine and placebo groups — for example, in the type of transplant, with fewer lung transplants and more abdominal organ transplants in the vaccine group than in the placebo group.

The comment is significant because COVID-19 infections begin in the respiratory tract, and therefore, an effective immune response from a lung transplant recipient at the outset is essential.

In the end, they pointed out that the study is short. The following is the summary of their editorial

Although antibody levels increased impressively after the third dose of mRNA-1273, trial follow-up was short-term.

Continued monitoring of the participants in this trial and of those in prospective nonrandomized studies will be important.

Although some may infer from these data that solid-organ transplant recipients should routinely receive a third vaccine dose, additional randomized trials will be key to learning how to better care for solid-organ transplant recipients during this pandemic.

That editorial was published on August 12, 2021.

Lo and behold! The FDA approved the Moderna and Pfizer shots as a booster shot on the same day!

The FDA based their decision for immune-compromised people on a 42-day study! Seriously!

Part of the letter

What are the criteria for the Emergency use Authorization? From the FDA letter again, emphasis are mine.

I. Criteria for Issuance of Authorization

I have concluded that the emergency use of Moderna COVID‑19 Vaccine for the prevention of COVID-19 when administered as described in the Scope of Authorization (Section II) meets the
criteria for issuance of an authorization under Section 564(c) of the Act, because:

A. SARS-CoV-2 can cause a serious or life-threatening disease or condition, including severe respiratory illness, to humans infected by this virus;

B. Based on the totality of scientific evidence available to FDA, it is reasonable to believe that Moderna COVID‑19 Vaccine may be effective in preventing COVID-19, and that, when used under the conditions described in this authorization, the known and potential benefits of Moderna COVID‑19 Vaccine when used to prevent COVID-19 outweigh its known and potential risks; and

C. There is no adequate, approved, and available alternative to the emergency use of Moderna COVID-19 Vaccine to prevent COVID-19.

No adequate, approved, and available alternative to prevent COVID-19? Maybe the FDA should read:

Take away message

The decision to have a vaccine is between the patient and their doctor—informed consent or knowing and balancing the risk and benefits factors in making that personal decision.

Medical studies presented as “data,” “evidence,” and “science” should be scrutinized. That is better than relying on mass media for health education.

Future policies to be made by the CDC are telegraphed from GOV.UK. The same website that proposed the shielding approach.

Saint Maximilian Kolbe

Today, August 14, is the feast day of St. Maximilian Kolbe. The Polish Conventual Franciscan Friar was sent to the Auschwitz concentration camp for hiding 3,000 Polish and Jewish refugees in a shelter at his friary.

He was put to death by the Nazis by lethal injection.

Knowledge about Covid-19 is rapidly evolving. Information may update as new studies are made. Stay current by subscribing. Feel free to share and like.

Don’t Get Sick!

References:

Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients
Third Time’s a Charm — Covid-19 Vaccine Hope for Solid-Organ Transplant Recipients.
FDA EUA letter to Pfizer
FDA letter to Moderna granting EUA for a third shot
Lee WS, Wheatley AK, Kent SJ, DeKosky BJ. Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nat Microbiol. 2020 Oct;5(10):1185-1191. doi: 10.1038/s41564-020-00789-5. Epub 2020 Sep 9. PMID: 32908214.

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