Duty to Warn by Gary Kohls, M.D.
The NIAID/Bill Gates-funded Moderna and Its Fast-tracked, Experimental SARS-CoV-2 Vaccine Phase I Preliminary Trial Shows that Large Percentages of the Subjects had Significant Adverse Reactions
But every report on the trial that was published in the mainstream media and financial press totally ignored the adverse effects, focusing instead on the fact that (essentially irrelevant) neutralizing antibodies had been produced
The trial consisted of a tiny number (45) of young (age 25 – 41), healthy, Caucasians. No infants, children, adolescents or anybody over the age of 41 were involved!
The fast-tracked trial began on March 16, 2020 (!), with all reagents for the vaccine having been fully developed by the start-up vaccine corporation Moderna, the majority of shares of which are reported to be held by the National Institutes Of Health
Funding for the manufacture of mRNA-1273 phase 1 material was provided by Bill Gates’ Coalition for Epidemic Preparedness Innovation (CEPI)
Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. The adverse effects that occurred in less than 50 % were not published in this report (!)
Moderna’s share price rose significantly following the release of the Phase I Data
Conflict of interest revelations for the authors was obscured
The excerpts of the article below were selected by Gary G. Kohls, MD
(Bolding and italicizations below by Dr Kohls)
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An mRNA Vaccine against SARS-CoV-2 — Preliminary Report
L.A. Jackson, E.J. Anderson, N.G. Rouphael, P.C. Roberts, M. Makhene, R.N. Coler, M.P. McCullough, J.D. Chappell, M.R. Denison, L.J. Stevens, A.J. Pruijssers, A. McDermott, B. Flach, N.A. Doria-Rose, K.S. Corbett, K.M. Morabito, S. O’Dell, S.D. Schmidt, P.A. Swanson II, M. Padilla, J.R. Mascola, K.M. Neuzil, H. Bennett, W. Sun, E. Peters, M. Makowski, J. Albert, K. Cross, W. Buchanan, R. Pikaart-Tautges, J.E. Ledgerwood, B.S. Graham, and J.H. Beigel, for the mRNA-1273 Study Group*
Published in the New England Journal of Medicine – July 14, 2020
DOI: 10.1056/NEJMoa2022483
https://www.nejm.org/doi/pdf/10.1056/NEJMoa2022483?articleTools=true
ABSTRACT
BACKGROUND
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.
METHODS
We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.
RESULTS
After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group).
After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens.
Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site.
Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.
CONCLUSIONS
The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified.
These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (Covid-19).1 The urgent need for vaccines prompted an international response, with more than 120 candidate SARS-CoV-2 vaccines in development within the first 5 months of 2020.2 The candidate vaccine mRNA-1273 is a lipid nanoparticle–encapsulated, nucleoside-modified messenger RNA (mRNA)– based vaccine that encodes the SARS-CoV-2 spike (S) glycoprotein stabilized in its prefusion conformation. The S glycoprotein mediates host cell attachment and is required for viral entry3 ; it is the primary vaccine target for many candidate SARS-CoV-2 vaccines.4-7 We conducted a first-in-human phase 1 clinical trial in healthy adults to evaluate the safety and immunogenicity of mRNA-127 3. Here we report interim results of the trial.
<<SNIP>>
RESULTS
Trial Population
The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig. S1). Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second vaccination window owing to isolation for suspected Covid-19 while the test results, ultimately negative, were pending. All continued to attend scheduled trial visits. The demographic characteristics of participants at enrollment are provided in Table 1.
Vaccine Safety
No serious adverse events were noted, and no prespecified trial halting rules were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination.
After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group; all were mild or moderate in severity(Fig. 1 and Table S2).
Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events.
None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever; one of the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe.
(Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.)
Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common.Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site.
Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3).
DISCUSSION
The two-dose vaccine series was generally without serious toxicity; systemic adverse events after the first vaccination, when reported, were all graded mild or moderate. Greater reactogenicity followed the second vaccination, particularly in the 250-μg group. Across the three dose groups, local injection-site reactions were primarily mild. This descriptive safety profile is similar to that described in a report of two trials of avian influenza mRNA vaccines (influenza A/H10N8 and influenza A/H7N9) that were manufactured by Moderna with the use of an earlier lipid nanoparticle capsule formulation11 and is consistent with an interim report of a phase 1–2 evaluation of a Covid-19 mRNA vaccine encoding the S receptor-binding domain.6
Those studies showed that solicited systemic adverse events tended to be more frequent and more severe with higher doses and after the second vaccination.
Previous experience with veterinary coronavirus vaccines and animal models of SARS-CoV and MERS-CoV infection have raised safety concerns about the potential for vaccine-associated enhanced respiratory disease.
These events were associated either with macrophage-tropic coronaviruses susceptible to antibody-dependent enhancement of replication or with vaccine antigens that induced antibodies with poor neutralizing activity and Th2-biased responses.31
Reducing the risk of vaccine-associated enhanced respiratory disease or antibody-dependent enhancement of replication involves induction of high-quality functional antibody responses and Th1-biased T-cell responses.
Studies of mRNA-1273 in mice show that the structurally defined spike antigen induces robust neutralizing activity and that the gene-based delivery promotes Th1-biased responses, including CD8 T cells that protect against virus replication in lung and nose without evidence of immunopathology.32 It is important to note that mRNA-1273 also induces Th1-biased CD4 T-cell responses in humans.
Additional testing in animals and ongoing T-cell analysis of clinical specimens will continue to define the safety profile of mRNA-1273. These safety and immunogenicity findings support advancement of the mRNA-1273 vaccine to later-stage clinical trials.
Of the three doses evaluated, the 100-μg dose elicits high neutralization responses and Th1-skewed CD4 T cell responses, coupled with a reactogenicity profile that is more favorable than that of the higher dose.
A phase 2 trial of mRNA-1273 in 600 healthy adults, evaluating doses of 50 μg and 100 μg, is ongoing (ClinicalTrials.gov number, NCT04405076).
A large phase 3 efficacy trial, expected to evaluate a 100-μg dose, is anticipated to begin during the summer of 2020.
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The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does any mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Moderna provided mRNA-1273 for use in this trial but did not provide any financial support. Employees of Moderna collaborated on protocol development, significantly contributed to the Investigational New Drug (IND) application, and participated in weekly protocol team calls.
The National Institute of Allergy and Infectious Diseases (NIAID) ultimately made all decisions regarding trial design and implementation.
Supported by the NIAID, National Institutes of Health (NIH), Bethesda, under award numbers UM1AI148373 (Kaiser Washington), UM1AI148576 (Emory University), UM1AI148684 (Emory University), UM1Al148684-01S1 (Vanderbilt University Medical Center), and HHSN272201500002C (Emmes); by the National Center for Advancing Translational Sciences, NIH, under award number UL1 TR002243 (Vanderbilt University Medical Center); and by the Dolly Parton COVID-19 Research Fund (Vanderbilt University Medical Center).
Funding for the manufacture of mRNA-1273 phase 1 material was provided by the Coalition for Epidemic Preparedness Innovation (CEPI).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the members of the mRNA-1273 Study Team (see the Supplementary Appendix) for their many and invaluable contributions, the members of the safety monitoring committee (Stanley Perlman, M.D., Ph.D. [chair], University of Iowa; Gregory Gray, M.D., M.P.H., Duke University; and Kawsar Talaat, M.D., Johns Hopkins Bloomberg School of Public Health) for their oversight; Huihui Mu and Michael Farzan for providing the ACE2-overexpressing 293 cells; and Dominic Esposito, Ph.D., Director of the Protein Expression Laboratory at the Frederick National Laboratory for Cancer Research, for providing the S-2P protein for the immunologic assays.
We also thank the participants themselves for their altruism and their dedication to this trial. The Emory University study team thanks the Georgia Research Alliance and Children’s Healthcare of Atlanta for their support. The Kaiser Washington study team thanks Howard Crabtree, R.Ph., and Sheena Mangicap, Seattle Pharmacy Relief, for their many years of support for vaccine trials.