Opened on March 07, 2021. Last updated by The POOG on March 15, 2021.
This article provides a factual basis for understanding mRNA vaccine development programs for the SARS-CoV-2 virus.
Two Issues to Clear Up
mRNA ‘Vaccines’ Are Not Really Vaccines
Persons engaged in the discussion around mRNA vaccines often claim that these are not ‘vaccines’ but are ‘genetic material preparations’ or some other term. The issue is one of semantics and in the overall discussion is unimportant. However, the Merriam-Webster dictionary definition of ‘vaccine‘ which we will use is:
: a preparation that is administered (as by injection) to stimulate the body’s immune response against a specific infectious disease:
a : an antigenic preparation of a typically inactivated or attenuated (see attenuated sense 2) pathogenic agent (such as a bacterium or virus) or one of its components or products (such as a protein or toxin)
b : a preparation of genetic material (such as a strand of synthesized messenger RNA) that is used by the cells of the body to produce an antigenic substance (such as a fragment of virus spike protein)
Part ‘b‘ of this definition – and it may have been recently updated to address this issue – is what we will go with. The Cambridge Dictionary does not have part ‘b‘ from above in its definition. I am aware of the other arguments against using the term ‘virus’. To dwell on them is to waste personal resources and expend the capital of one’s credibility.
I. R. Daniel argues that these mRNA products are medical devices by FDA definition rather than vaccines. Her error is in misunderstanding the definition of a device ‘component’. She does, however, give an extensive list of concerns associated with the vaccine which should be addressed before final marketing approval is given.
mRNA Are Currently Experimental Drugs.
The other issue is more difficult: namely that the mRNA vaccines are experimental. That they were at some point in the trial process described as ‘experimental’ is revealed in NIH documents and others. The FDA granted an “emergency use authorization (EUA) for … vaccine for the prevention of coronavirus disease 2019 (COVID-19) caused by … SARS-CoV-2” to Pfizer on December 11, 2020 and to Moderna on December 18, 2020.
This is not a final authorization for unrestricted marketing but an emergency use authorization only. As such, the vaccines must still be considered to be ‘experimental’ until final authorization is given which normally would be after phase 3 trials have finished.
The Standard Vaccine Development Protocol
The US Food and Drug Administration (FDA) has published a description, emphasis added, of “the typical process that FDA expects vaccine developers to follow to generate the information it needs to assess the safety and effectiveness of a vaccine to prevent an infectious disease“. Steps 1-3 are known as “the Pre-clinical phase“. After this, “Studies conducted in people are known as the Clinical Development stage and typically cover three phases under the oversight of FDA“. Steps are listed below.
- scientists conduct laboratory research to develop and test their idea for a vaccine candidate;
- in vitro testing is done on cell lines;
- in vivo testing is done in animals;
- Phase 1 clinical trial – Emphasis is on safety and generally includes 20–100 volunteers;
- Phase 2 clinical trial – The study include 100’s of people of varying demographics and characteristics with various dosages;
- Phase 3 clinical trial – The study include thousands of people. It generates critical information on effectiveness and additional important safety data.
- This final step is the FDA New Drug Application process. All the data is reviewed leading to the issue (or not) of marketing authorization.
There are other descriptions of the development process but all cover the same steps with slightly different grouping or organization of the stages. It is the last step of FDA review that is necessary, and after a successful final review, leads to commercial marketing authorization. The traditional vaccine development timeline would take at least 3 years but can take as long as 15 to 20 years. The FDA does have defined special case situations whereby the process may be accelerated.
Baden et al (2021) somewhat disingenuously describe Moderna’s program.
Within 1 year after the emergence of this novel infection that caused a pandemic, a pathogen was determined, vaccine targets were identified, vaccine constructs were created, manufacturing to scale was developed, phase 1 through phase 3 testing was conducted, and data have been reported.Baden et al (2021)
The problem with their enthusiastic statesmen is that the phase 3 trial was not conducted but is being conducted since it won’t finish until summer 2022 at the earliest.
Moderna In Vivo Trials
Moderna describes their approach to vaccine development on their own website.
Data on Moderna’s in vivo trials is very limited. They were conducted in parallel with phase 1 human trials and were begun around the same time. The timeline is hard to pin down since studies don’t give dates, but there are clues in some reports.
Corbett et al. (2020) studied the effect of the mRNA-1273 vaccine on 24 rhesus macaques divided into 6 study cohorts. Those given the vaccine in either of 2 strengths showed immunological responses similar to those found in the phase 1 human trial.
Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.)Corbett et al. (2020)
The vaccine and placebo injections were given at week 0 and week 4 (28 days apart). All candidates were challenged with the live virus 4 weeks later. Immunological assays were performed 2 days and 7 days after challenge.
It has been noted that in earlier coronavirus development attempts, the candidate animals died when challenged with the particular virus being tested. The cause was a cytokine storm caused by pathogenic priming by the vaccine. This study does not report results for longer than 1 week after challenge. There was no immediate severe immune response. It is unknown how long the study continued but the reference to sections of lung tissue examined suggests that the monkeys did not live to a ripe old age.
Another experiment using 35 rhesus macaques was conducted by researchers mostly from Harvard. They generated six DNA vaccines expressing different SARS-CoV-2 spike (S) variants. Using these, they demonstrated similar efficacy in immunological response in the non-human primates, to the Moderna trial. No pathological results were reported.
The in vivo studies would suggest that similar results would be expected from other mRNA vaccines like the Pfizer BNT162b2. The general result is that vaccinated monkeys cleared the virus faster than non-vaccinated ones and their viral load was lower, lessening their ineffectiveness.
For more information on trial progression and results, go to the literature or monitor Moderna’s Publications site.
A concern has been expressed by some that no proper followup will be done on the administration of these vaccines. Indeed such may not be possible in an organized manner. The global distribution of the vaccines to date, has been haphazard.
The US has a voluntary vaccine side-effect reporting system called the Vaccine Adverse Event Reporting System (VAERS). It is co-managed by the Centers for Disease Control and Prevention (CDC) and the FDA. As of March 6, 966 deaths due to the vaccines have been reported. Since reporting is voluntary and the system may not be widely known, this has to be the low end of actual death records.
An ongoing concern is the effectiveness of these first generation vaccines against new variants.
The Technical Concerns with These Vaccines
Here is a video, Mass Vaccination in a Pandemic – Benefits versus Risks | McMillan Research, that I cannot embed so you will have to click the link. It discusses risks, particularly in the medium to long term, that should be taken seriously.
- Vaccine Development – 101. FDA. December 14, 2020.
- Corbett KS, Flynn B, Foulds KE, et al. (2020). Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med. October 15, 2020. 383:1544-1555. DOI: 10.1056/NEJMoa2024671.
- Boodman E. Researchers rush to test coronavirus vaccine in people without knowing how well it works in animals. STAT. March 11, 2020.
- Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science, Vol. 369, Issue 6505, pp. 812-817. August 14, 2020. DOI: 10.1126/science.abc4776.
- Yu J, Tostanoski LH, Peter L, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques.Science, Vol. 369, Issue 6505, pp. 806-811. August 14, 2020. DOI: 10.1126/science.abc6284.
- Farber C. Adverse Incident Reports Show 966 Deaths Following Vaccination for COVID-19. Epoch Times. March 6, 2021.
- Staff. mRNA Platform: Enabling Drug Discovery & Development. Moderna. Accessed on March 07, 2021.
- Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med, 384:403-416. February 4, 2021. DOI: 10.1056/NEJMoa2035389.
- Staff. Moderna’s Fully Enrolled Phase 3 COVE Study of mRNA-1273. Moderna. Accessed on March 07, 2021.
- Moderna Phase 2 Approved, And Other News: The Good, Bad And Ugly Of Biopharma. Seeking Alpha. May 10, 2020.
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- Experimental coronavirus vaccine is safe and produces immune response. NIH. July 21, 2020.
- Vaccine Types. NIH. Accessed march 08, 2021.
- Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against SARS-CoV-2 — Preliminary Report. N Engl J Med; 383:1920-1931. November 12, 2020. DOI: 10.1056/NEJMoa2022483.
- Galford C. In vitro neutralization studies confirm lessened Moderna vaccine effectiveness against COVID-19 mutations. HPN. February, 2021.
- How the FDA Drug Approval Process Works. DPAC. February 20, 2018.
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- Anderson LA. FDA Drug Approval Process. Drugs.com. May 27, 2019.
- Pfizer-BioNTech COVID-19 Vaccine. FDA. Content current as of: March 02, 2021.
- Moderna COVID-19 Vaccine. FDA. Content current as of: March 02, 2021.