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On Dec. 1, the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices made a recommendation for health care professionals and residents of long-term care facilities to get priority vaccination with the pending Pfizer and Moderna SARS-CoV2 vaccines.

The Pfizer vaccine will be reviewed by the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Dec. 10 and materials will be available on Dec. 8. The Moderna vaccine will be reviewed by the FDA on Dec. 17. Each company has applied for Emergency Use Authorization. Under such authorization, these vaccines cannot be legally mandated by states but private entities may mandate them and long-term care residents may be required to be vaccinated with COVID-19 vaccines as a condition of residency.

In the U.S, the average age of entry to a nursing home is 79, 39% of nursing home residents are over age 85 and 83.5% are over age 65. Approximately 25% of nursing home residents are Black, Hispanic or other minorities. The residents of long-term care facilities include 1.3 million in skilled nursing, 800,000 in assisted living and 900,000 in other residential care, which includes residential care communities, residences for people with developmental disabilities and state veteran’s homes. The total is approximately 3 million Americans.

COVID-19 has been devastating to these populations. COVID-19 deaths in these facilities are now over 100,000 or about 40% of the total U.S. mortality. According to the ACIP power point, the mortality among confirmed cases in skilled nursing homes through Nov. 15 was 14%. The confirmed case mortality rate in assisted living facilities was even higher at 20% in a sample of 23 states through Oct. 15.

There is no question that public health officials need to vigorously protect these vulnerable populations. However, it is important to look carefully at the data that is directly available in the vaccine clinical trials on older participants in order to make the best possible recommendations. If these vaccines are either less safe or less effective in frail elderly populations than hoped, the results of widespread vaccination could be catastrophic.

To date, there is essentially no published data on these vaccines in the relevant age groups for residential long-term care. In the stage ½ trial of the Pfizer vaccine BNT162B2 30 microgram dose that went on to the Phase 3 trial, there were 12 subjects in the 65-85 age group. All of them were white. The median age was 68 with a range from 65-74.

In the stage 1/2 trial of the Moderna vaccine, there were 10 subjects in the greater than or equal to 71 age group who received the 100 microgram dose that moved forward to the Stage 3 trial. All of them were white. The mean age in the group was 72.6 plus or minus 1.1.

Due to the nature of early trials, these were all healthy community-dwelling seniors who are not medically comparable to nursing home residents. In the early trials, the short-term (monitored for seven days) side effects and production of immune responses (antibodies and T-cells) were reasonable, but these results are uninformative for an older, frailer population. Both of these small populations reported fewer short-term side effects in these seniors compared to the younger adults which may be good or bad since many of the side effects measured (fever, redness, etc.) are associated with mounting an effective immune response to a vaccine. What remains completely unknown is what the immune responses will look like in older people with more comorbidities as immunosenescence increases with age.

What we need to know

As the U.S. Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) committee looks at the data from the large Stage 3 trials of both vaccines beginning next week, it will be critical to separate and investigate the participants who are actually relevant for making an Emergency Authorization Use approval of these vaccines for frail, elderly Americans.

Pfizer has reported that 45% of the Stage 3 population was in the 55-85 age range, but there is a significant difference in the immune competence of a 55 year-old vs. an 85 year-old and the age breakdown of the cohort over 55 will need careful scrutiny. What proportion of this group was over 65? What proportion was over 75 and were there enough subjects in these groups to do statistical analysis? Were different racial groups adequately represented? What was the actual number of, for example, 80 plus year-olds with health conditions who participated and what were their outcomes for safety and efficacy?

The inclusion and exclusion criteria for the Pfizer Stage 3 trial would still promote a bias towards healthy, community-living elderly as it included the following requirements (among others).

Inclusion Criteria:

  • Male or female participants between the ages of 18 and 55 years, inclusive, 65 and 85 years, inclusive, or >12 years, inclusive, at randomization (dependent upon study phase).
  • Participants who are willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, lifestyle considerations, and other study procedures.
  • Healthy participants who are determined by medical history, physical examination, and clinical judgment of the investigator to be eligible for inclusion in the study.
  • Participants who, in the judgment of the investigator, are at risk for acquiring COVID-19.
  • Capable of giving personal signed informed consent.

These inclusion criteria will likely have eliminated the possibility of long-term care residents participating in the trials as they remain locked-down in many parts of the country. Participants appear to have needed to commit to seven visits to participate (for two vaccinations and follow-ups). The stipulation for “healthy participants” is also limiting as it relied on the clinical judgment of the investigator, as is the personal signed informed consent which would rule out patients with dementia.

Exclusion criteria:

  • Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
  • History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s).
  • Receipt of medications intended to prevent COVID 19.
  • Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination.
  • Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.
  • Individuals who receive treatment with immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study.
  • Receipt of blood/plasma products or immunoglobulin, from 60 days before study intervention administration or planned receipt throughout the study.

These exclusion criteria would eliminate any senior with depression, anxiety, cancer, autoimmune disorders or COPD/asthma.

Moderna’s press reports that 25% of the participants in its Stage 3 trial were over the age of 65. Again, it will be important to separate that cohort into the relevant age groups to look at Emergency Use Authorization in long-term care facilities. Similarly, the inclusion and exclusion criteria will have limited the relevance of even those subjects who are in the appropriate age range to inform policy.

Inclusion criteria: Participants are eligible to be included in the study only if all the following criteria apply:

  • Adults, ≥ 18 years of age at time of consent, who are at high risk of SARS-CoV-2 infection, defined as adults whose locations or circumstances put them at appreciable risk of exposure to SARS-CoV-2 and COVID-19.
  • Understands and agrees to comply with the study procedures and provides written informed consent.
  •  Able to comply with study procedures based on the assessment of the Investigator.
  • Healthy adults or adults with pre-existing medical conditions who are in stable condition. A stable medical condition is defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 3 months before enrollment.

Exclusion criteria: Participants are excluded from the study if any of the following criteria apply:

  • Is acutely ill or febrile 72 hours prior to or at Screening. Fever is defined as a body temperature ≥ 38.0°C/100.4°F. Participants meeting this criterion may be rescheduled within the relevant window periods. Afebrile participants with minor illnesses can be enrolled at the discretion of the investigator.
  • Demonstrated inability to comply with the study procedures.
  • Known or suspected allergy or history of anaphylaxis, urticaria, or other significant adverse reaction to the vaccine or its excipients.
  • Bleeding disorder considered a contraindication to intramuscular injection or phlebotomy.
  • Has received or plans to receive a non-study vaccine within 28 days prior to or after any dose of IP (except for seasonal influenza vaccine which is not permitted within 14 days before or after any dose of IP, see Section 6.4.3).
  • Immunosuppressive or immunodeficient state, asplenia, recurrent severe infections (HIVpositive participants with CD4 count ≥350 cells/mm3 and an undetectable HIV viral load within the past year [low level variations from 50-500 viral copies which do not lead to changes in antiretroviral therapy [ART] are permitted]).
  • Has received systemic immunosuppressants or immune-modifying drugs for >14 days in total within 6 months prior to Screening (for corticosteroids ≥ 20 mg/day of prednisone equivalent).
  • Has received systemic immunoglobulins or blood products within 3 months prior to the day of screening.

While it is obviously important to clearly define (include and exclude) those participants who might compromise the general applicability of a clinical trial for the general public, it is equally important to not extrapolate too far beyond the data that will actually be presented at the VRBPAC meetings.

The bottom line is that we must be very critical of the data from the Stage 3 Trials of the coronavirus vaccines and make only those recommendations that are truly supported by science. There is tremendous political pressure to get everyone vaccinated so that “things can return to normal”. However, if these vaccines cause more significant side effects in unhealthy, frail, elderly populations than expected, because we haven’t actually studied this group, then the risk/benefit equation becomes fraught and we might actually put more pressure on our health care system. Equally, if the efficacy of these vaccines at providing protection from infection in long-term care facilities is not sufficient in these groups, then it is possible that vaccination will still allow the spread of SARS-CoV2 amongst residents as lockdowns are eased. Policy makers must consider the actual data available and make sound, measured recommendations, including resisting the impulse to rush these vaccines to a population that has not been fully studied. The intent to study these vaccines after they have been given is important, but it cannot replace careful scrutiny up front.

While Children’s Health Defense focuses on children’s health, our senior family members and friends need and deserve attention as well. That thoughtful care has not always been present during the epidemic. Families are struggling to balance safety of loved ones, care, social contact, school and jobs. The participation of grandparents and other elderly family members in children’s lives has a significant positive impact on our children’s physical and mental health. Ensuring their well-being helps us all.

The three power points from the CDC ACIP presentations are available here. Public comments may be provided to the FDA’s VRBPAC committee by Dec. 4 for submission to the committee. Comments submitted between Dec. 4 and Dec. 9 will still be considered by the FDA.