skip to Main Content

COVID-19 Vaccination trial review

Lets look into mRNA vaccines and the COVID -19 vaccine paper release by NEJM in regards to the Pfizer study and review the current literature, make some comparisons and see if we can have some objective data.

The COVID Vaccines being released are mRNA. What is the significance of this? What does it mean?

mRNA (messenger RNA) as a therapeutic (towards targeted cancer therapies) was first promoted in 1989 after the development of a broadly applicable in vitro transfection technique. (1) Only a couple of years later, mRNA was advocated as a vaccine platform, perhaps being ideal in the sense that it brings together the immunological features of live attenuated vaccines such as endogenous antigen expression and T cell induction with those of killed or subunit vaccines like defined composition and safety. (3,4) Compared with DNA as a therapeutic or more specifically as a vaccine, mRNA offers strong safety advantages – as the minimal genetic construct it harbors only the elements directly required for expression of the encoded protein. (1) To be translated and elicit an antigen-specific immune response, an mRNA-vaccine has to reach the cytosol of target cells. However, as opposed to DNA vaccines, RNA vaccines in theory only have to cross the plasma membrane, but not the nuclear envelope. There is a much more complex mechanism that this has been noted to occur which is less relevant to this article – suffice to say that mRNA mechanisms for delivery to cells have been an issue more specifically in cancer studies having trouble reaching the cytosol of tumor cells. In earlier mRNA vaccine development articles it has been postulated that direct delivery into the cytosol would certainly enhance antigen expression however the lack of interaction with endosomal (inside the cell) RNA receptors may severely weaken immunostimulation by the vaccine and this issue would likely have to be addressed. (1,2,3,18)

OK, so mRNA if delivered into the cytosol of cells could work as a vaccine, how does the COVID vaccine deliver the mRNA if the injection is IM?

They came up with a lipid nanoparticle that protects and preserve the mRNA from degradation and delivers it into the cell itself through a translocation process. The lipid nanoparticles must be stored at extremely low temperatures (-70 C / 2 – 8 C for 5 days ) (4). After the mRNA enters the cells, the subsequent interaction with endosomal RNA then takes the mRNA and begin to synthesize this information to produce the spike protein portion of the SARS CoV-2 virus. This mechanism for delivery and preservation is currently used by the Shigrix (TM) vaccine for shingles (VZV) in terms of similarity.

So the Vaccine didn’t synthesize protection to the entire coding of the virus but instead only a spike protein?

Yes, they used a nucleoside-modified RNA (modRNA) encoding a particular SARS-CoV-2 full-length spike (thought to elicit the most antigenic response), modified by two proline mutations to lock it in the prefusion conformation in vitro. In the phase 2 trials for both Moderna and Pfizer this spike appeared to elicit high SARS-CoV-2 neutralizing antibody titers and robust antigen-specific CD8+ and Th1-type CD4+ T-cell responses, in theory inducing both humoral and cellular immunity (T-cell immunity thought to last longer), leading them to progress to the phase 3 trials.

OK so the newest shingles vaccine is mRNA similar to the COVID vaccines, what is the efficacy of that and what can I take from those trials?

Well, the Merck trials used similar lipid nanoparticle (LNP) formulated mRNA encoding VZV gE antigen and compared it to well-established platforms of live attenuated VZV virus vaccinations. They found that a 100-200 μg mRNA dose induced the same immunologic response compared to two 50 μg protein doses of VZV gE protein live attenuated virus. The published statistics are ~97% effective at preventing shingles outbreaks in adults >50 with the mRNA version as opposed to the prior live attenuated version that only reduced shingles outbreaks by 51% and post-herpetic neuralgia by 67%. (6,7,25) The caveat – The vaccine was released in 2017, so long term data over whether immunity remains for a period of time is unknown, but it was still noted to be about 85% effective at the 4 year mark in mid 2020. In essence, the COVID vaccines are similar in this regard – we are unable to know how low immunity would last.

So what did the trials for the COVID vaccines demonstrate?

Pfizer – 43,448 participants received injections (21,720 received vaccine vs 21,728 received placebo). Of the 36,523 participants who had no evidence of existing or prior SARS-CoV2 infection – 8 cases of COVID-19 with onset at least 7 days after the second dose were observed in the vaccine group and 162 cases were observed in the placebo group. Efficacy after 2 doses was 95% (95% CI 90.3 to 97.6). The study was not designed to assess efficacy with only 1 dose but demonstrated 52% vaccine efficacy after single dose (95% CI 29.5 to 68.4%). Long term efficacy unknown (4,8,9,11,12).

Moderna- currently >30,000 enrollment in phase III trials. Early results claim >95% efficacy. Final data pending.

Others- unpublished thus far, including a Russian trial.

Ok, I’ve read the immunity and efficacy data, but what about the side effects and downstream effects?

Certainly. Lets look over the published data on this.

In the Pfizer study 27% of vaccine recipients vs 12% placebo reported an adverse event or a related adverse event (21% vs 5%). Most commonly pain at injection site, fever, headache, myalgia, lymphadenopathy. Frequency of any severe systemic event after 1st dose was ≤0.9% – this means anaphylaxis or similar. Incidence of serious adverse events was similar between groups (Vaccine 0.6% vs Placebo 0.5%). 4 serious adverse events were reported in the vaccine group: Shoulder injury from vaccine administration, severe axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and leg paresthesias. 2 vaccine recipients died from adverse cardiac events (MI, cardiac arrest) but 4 died in the placebo group from MI, hemorrhagic stroke and 2 from unknown causes. No deaths were considered related to the vaccine or placebo. (4,5,6)

What about the news article and FDA press release that says to watch for Bells Palsy after vaccination?

https://www.usnews.com/news/health-news/articles/2020-12-15/fda-recommends-watching-vaccine-recipients-for-bells-palsy

The Pfizer study noted 4 cases of Bells palsy in the trial group, and 0 in the placebo group. The general incidence of Bells palsy in the general population is approximately 23 cases in 100,000. If this is extrapolated to the 38k enrollment of the Pfizer study should amount to 11 in 100,000. Bells is thought to be related to HSV-1, and statistics show ~48% of the US population has HSV-1 infection/antibodies based on the 2016 published data, so overall it seems to be multifactorial and unclear if the COVID vaccine has direct causation, however the incidence of this in the vaccine trial is less than general statistics.

Overall the Pfizer study is set to be a 2 year study with follow-ups, antibody titer and clinical evaluations on efficacy during this time. As it is early, it is unclear in regards to other downstream effects, which is a limitation of an early trial and unprecedented timeline of the vaccine release due to FDA emergency authorization. (29)

Overall thoughts on the Pfizer study

Well, the study had relatively balanced participants in terms of age, sex, baseline BMI, and the presence of coexisting conditions. Overall the two-dose regimen developed by Pfizer seems to be both safe with mostly minor adverse effects and effective against protecting against COVID-19 per the NEJM article from the data noted thus far. “Stable” Chronic medical conditions were included, and populations of HIV, HCV, HCB etc. Age <16 was not represented and there was no data or enrollment of pregnant patients in the initial data however the paper does discuss further data and trials to be reporting efficacy and safety in younger age groups, pregnant, and immunocompromised patients. Currently this is unknown overall for now. Interestingly initial recommendations noted that participants in the phase II trial should not try to become pregnant/try to conceive, so the prior statement is contrasting and somewhat confusing. 82.9% of the trial participants were identified as white/caucasian, and this does pose some implications in terms of efficacy data across race/ethnicity and epidemiology standpoints, as higher mortality and morbidity statistics have been demonstrated in minorities.(28) After vaccination very few cases of severe COVID-19 were seen making it difficult to draw any definitive conclusions about the rare cases that occur in vaccinated participants or sequelae from getting COVID-19 infection after being vaccinated. Of course a major issue with the study is that it is unclear whether the vaccine would prevent asymptomatic infection or asymptomatic transmission if a vaccinated person contracts subsequent COVID. Lastly – it is a pharmaceutical sponsored trial – which has additional implications.

References

  1. RNA Biol. 2012 Nov 1; 9(11): 1319–1330.doi: 10.4161/rna.22269
  2. Hilleman MR. Recombinant vector vaccines in vaccinology. Dev Biol Stand. 1994;82:3–20. [PubMed] [Google Scholar]
  3. Liu MA. Immunologic basis of vaccine vectors. Immunity. 2010;33:504–15. doi: 10.1016/j.immuni.2010.10.004. [PubMed] [CrossRef] [Google Scholar]
  4. https://www.nejm.org/doi/10.1056/NEJMoa2034577
  5. Polack FP et al. Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine. NEJM 2020. PMID: 33301246
  6. https://pubmed.ncbi.nlm.nih.gov/32703745/
  7. Vaccine. 2020 Aug 10;38(36):5793-5802. doi: 10.1016/j.vaccine.2020.06.062. Epub 2020 Jul 20.
  8. Heidi Ledford. (2020) US authorization of first COVID vaccine marks new phase in safety monitoring. Nature 588:7838, 377-378.
  9. Herb F Sewell, Raymond M Agius, Denise Kendrick, Marcia Stewart. (2020) Covid-19 vaccines: delivering protective immunity. BMJ, m4838.
  10. David Cyranoski. (2020) Arab nations first to approve Chinese COVID vaccine — despite lack of public data. Nature.
  11. Elisabeth Mahase. (2020) Covid-19: Pfizer vaccine efficacy was 52% after first dose and 95% after second dose, paper shows. BMJ, m4826.
  12. https://www.usnews.com/news/health-news/articles/2020-12-15/fda-recommends-watching-vaccine-recipients-for-bells-palsy
  13. Rubin Eric J., Longo Dan L.. (2020) SARS-CoV-2 Vaccination — An Ounce (Actually, Much Less) of Prevention. N Engl J Med DOI: 10.1056/NEJMe2034717.
  14. Johns Hopkins University Coronavirus Resource Center. COVID-19 dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. 2020 (https://coronavirus.jhu.edu/map.html. opens in new tab).
  15. World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19 — 11 March 2020 (https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020. opens in new tab).
  16. Centers for Disease Control and Prevention. COVID-19 information page (https://www.cdc.gov/coronavirus/2019-ncov/index.html. opens in new tab).
  17. Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med. DOI: 10.1056/NEJMoa2027906.
  18. Pardi N, Tuyishime S, Muramatsu H, et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release 2015;217:345-351.
  19. Karikó K, Muramatsu H, Welsh FA, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 2008;16:1833-1840.
  20. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-1263.
  21. Sahin U, Muik A, Vogler I, et al. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans. December 11, 2020 (https://www.medrxiv.org/content/10.1101/2020.12.09.20245175v1. opens in new tab). preprint.
  22. Food and Drug Administration. Guidance for industry: emergency use authorization for vaccines to prevent COVID-19. October 2020 (https://www.fda.gov/media/142749/download. opens in new tab).
  23. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Ann Intern Med 2020;172:577-582.
  24. Haynes BF, Corey L, Fernandes P, et al. Prospects for a safe COVID-19 vaccine. Sci Transl Med 2020;12(568):eabe0948-eabe0948.
  25. Cowling BJ, Perera RAPM, Valkenburg SA, et al. Comparative immunogenicity of several enhanced influenza vaccine options for older adults: a randomized, controlled trial. Clin Infect Dis 2020;71:1704-1714.
  26. Food and Drug Administration. Shringrix (zoster vaccine recombinant, adjuvanted) product information. 2019 (https://www.fda.gov/vaccines-blood-biologics/vaccines/shingrix. opens in new tab).
  27. https://www.newscientist.com/article/2259939-moderna-coronavirus-vaccine-trial-produces-best-results-yet/
  28. Frank Lodeserto MD, “COVID-19 Update: The COVID-19 Pfizer Vaccine”, REBEL EM blog, December 15, 2020. Available at: https://rebelem.com/covid-19-update-the-covid-19-pfizer-vaccine/.
  29. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-vaccines

Stefan Meyering DO FAAEM FACEP

Academic EM Attending Physician | APD @ Ft Worth EM | Director of Translational Research & Education | Interests: Graduate Medical Education, Risk Management and Legal Medicine, POCUS, Free Open Access Medical Education (FOAMed), Physician Wellness

This Post Has 0 Comments

Leave a Reply

Your email address will not be published. Required fields are marked *

Back To Top
Search