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Response to an MRNA Vaccine against SARS-CoV-2-Preliminary Report
Morgan Jayne, MD, Div. of Quality and Safety, Clinical Director/Covid Task Force, Piedmont Healthcare, Inc., Atlanta, GA And Cooke David, MD, Section of General Thoracic Surgery, University of California, Davis Health, Sacramento, CA; Kpodonu Jacques, MD, Div. of Cardiothoracic Surgery, Beth Israel Medical Center/Harvard Medical School, Boston, MA
Morgan Jayne, MD, Div. of Quality and Safety, Clinical Director/Covid Task Force, Piedmont Healthcare, Inc., Atlanta, GA
Nearly 4 million people in the United States are known to have been infected with SARS-CoV-2.
In the face of a new disease in dire need of proven treatments, every patient not offered enrollment in a well-designed, well-conducted study represents a missed opportunity to advance scientific knowledge, develop therapeutic strategies, and ultimately improve care for everyone. Despite the truncated timelines currently being heralded to create vaccines, the development of new vaccines and medicines is both an arduous and lengthy endeavor. It, of course, would not be possible at all without human subjects who are encouraged to volunteer to participate. These trials determine early, the safety of the compound being studied, then later the efficacy. Suppose these results in safety and efficacy are both accurate and applicable to all patients. In that case, the demographics of subjects enrolled must mirror the demographics of the population affected by the disease. It is, therefore, essential that the development of vaccines and medicines that will be given to varying populations of varying ages, and varying ethnicities, accurately reflect not only the effectiveness but the potential harm to all groups as well.
Racial disparities have become central in the national conversation about COVID-19, with African Americans suffering COVID-19 infection and related death disproportionately. Bassett et al. note that African American populations have lost 48,204 years from COVID-19 death than 33,446 years for White persons, despite White Americans representing a much larger percentage of the population.
Differences in health outcomes based on race and ethnicity are real and have been extensively documented (1). African Americans make up 13.4 percent of the U.S. population, yet only 5 – 7 percent of clinical trial participants nationally. This leads to the largely accepted and non-scientific practice of extrapolating data (that is generally gathered on White male subjects), to all other populations, including women. Jackson et al. (2) report in their recent journal publication preliminary findings from a trial to evaluate an mRNA SARS-CoV-2 vaccine’s safety and immunogenicity to prevent COVID-19 that is currently scouring the nation. The trial design is elegant and straightforward, with early results of this trial encouraging. In the report by Jackson et al., 45 adult patients comprised 3 different arms in open-label design were between the ages of 18 -55 years of age and were segregated into one of the three groups receiving two doses each of the vaccines at 28-day intervals. Group 1 received two doses of 25 ug each, Group 2 received two doses of 100 ug, and Group 3 received two doses of 250ug. We note that only 2 African Americans were enrolled in this trial, which equates to 4 percent participation, compared to the 13.4 percent representation of the U.S. populace.
“Differences in health outcomes based on race and ethnicity are real and have been extensively documented”
Additionally, and perhaps tragically, both African American subjects were enrolled in the same dose group (100 ugs). Therefore there is no information at all on African American responses in the two other dose arms. Additionally, following the first vaccination, solicited systemic adverse events were reported as n=5 (33 percent) in the 25 ug group, n=10 (67 percent) in the 100 ug group, and n = 8 (53 percent) in the 250 ug group, identifying the only group with African American patients as also having the greatest reported events.
Following the second vaccination, solicited systemic adverse events were reported as n=7 (54 percent) in the 25 ug group, n = 15 (100 percent) in the 100 ug group, and n=14 (100 percent) in the 250 ug group due to a missed window by one of the participants. Interestingly, since the 100ug group demonstrated 100 percent of systemic adverse events (SAEs) following the second dose, it is concluded that 100 percent of all African Americans enrolled in this trial also had systemic SAEs following the second dosing early trial. Is that of significance? Statistically, it is not; yet morally, we would argue that it is. Further, this will not be elucidated clearly ahead of the rush toward FDA approval without more significant numbers.
Moreover, it is not lost on the authors herein that while COVID-19 disproportionately impacts African Americans and other minority communities, the earliest vaccine trial is being developed almost entirely with the profile of Whites. This pattern is also noted time and again in critical oncology trials, including trials targeting cancers that disproportionately affect African Americans. Further, the authors of this trial reveal that the “evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern”. However, without adequate representation of African Americans, we do not know if that holds for this population. And so, this begets the question of whether a vaccine is being developed for COVID-19 that cannot be confidently and scientifically applied to African Americans because they are woefully under-represented in this trial?
Historically, we know that African American patients have greater participation (3) in clinical trials if the following issues are actively identified and addressed:
1.Lack of culturally concordant leadership representation within the Research infrastructure of hospital systems. The role of formal decision-making leadership roles and advocacy within Research divisions is crucial and cannot be overstated. It would be interesting for Jackson et al. to comment on whether African American researchers were part of the study design.
2.Lack of knowledge and information dissemination. African Americans are excluded from reliably receiving information on clinical trials. Minority patients are willing to participate in clinical trials but are not asked to participate as often as White patients. Did Jackson et al. actively seek diverse participation? And if so, what was there a methodology to reach out to diverse populations?
3. Cultural Competence - When the quality of care is equivalent, patients prefer physicians of the same ethnicity or race as themselves. Communicating in a transparent, culturally relevant manner aids acceptance. When the invitation to consent to a trial comes from a trusted physician, the likelihood of participation is increased. Has Jackson et al. undergone cultural competency or implicit bias training in anticipation of this study?
4.Lack of engagement between academic researchers and the African American community. Physicians are more likely to refer people to clinical trials if they have a working relationship with the hospital/university conducting the clinical trial.” African American physicians are less likely to have close relationships with academic centers and are also less likely to be recruited and to have experience as clinical investigators. Did Jackson et al. utilize the community outreach centers likely available at the medical centers identified in author affiliations?
5.Trust is paramount and is further eroded not only by the lack of African Americans in Research Leadership roles within hospitals but also by the near absence of African American physicians as Principle Investigators leading the participation in clinical trials. Adding to that, the historical atrocities committed against African Americans in the name of ‘research’, and workforce diversity emerges as a critical target of a call to action. Did Jackson et al. identify study sites with African American presence in leadership and at the level of coordinators?
6. SDOH (Social Determinants of Health) – long term commitments, travel, inconvenience of trial locations, childcare, time off from work, costs. Did Jackson et al. implement strategies to mitigate the socio-economic barriers to many eligible study participants of color?
7.Lack of focus by Pharma Companies. Does Moderna, Inc. identify the importance of including diverse populations in its mission, vision, and goals?
8. Inequitable access to healthcare. Summation of 1 – 7.
As COVD-19 has exposed so starkly, African Americans carry some of the highest healthcare burdens in the United States. Lack of inclusion of African Americans into clinical trials further widens the health disparity gap. Equitable participation in clinical trials is an essential tool that African Americans are systemically denied contributing to health care disparities. Unfortunately, this critical trial appears to be giving us more of the same and perpetuates structural racism in public health and clinical research.
The authors indicate that a planned phase 3 trial of this mRNA SARS-CoV-2 vaccine is imminent; the trial will require thousands of subjects to confirm the safety of the vaccine and show statistically robust efficacy in preventing COVID--19. The pandemic compounds the operational complexity inherent in a large study; efficacy can be determined only if there is a match between the location of vaccinated participants and pandemic hot spots. We challenge the authors to include African Americans clinicians, scientists, and patient stakeholders in the design, recruitment plan, and implementation of the phase 3 trial. In crisis comes opportunity. Jackson et al. have a unique opportunity to show the way of dismantling structural racism in clinical research. #BlackLivesMatter