Transmission reduction tests in clinical trials, focus on the Pfizer COVID19 vaccine
Summary:
- Reduction of SARS-CoV-2 transmission is a major goal in the management of outbreaks and pandemics.
- Initial Pfizer/BioNTech clinical trials did not evaluate SARS-CoV-2 transmission but followed EMA’s recommendations.
- Clinical trials of vaccines do not usually study transmission. Instead, the reduction of infections is employed as a standard outcome.
Recently, the lack of testing for the reduction of SARS-CoV-2 transmission during the PFizer/BioNTech BNT162b2 (Comirnaty) vaccine clinical trials has gained a lot of attention. The issue was discussed widely on social media platforms such as Reddit or YouTube, as well as in public spaces like the European Parliament (1). This has reopened the discussion about the approval by the regulatory agencies in early 2021. In this article, we will clarify what pathogen transmission means and why it is important to discuss it in the pandemic context. Moreover, we will present official recommendations of the European Medicines Agency and the Food & Drug Administration for the Covid-19 vaccines and primary endpoints established in the clinical trial protocol from Pfizer/BioNTech. This will shed light on the approval of the existing vaccines against SARS-CoV-2.
Transmission of a pathogen is the process of spreading of an agent (virus, bacteria, parasites) among hosts. This can happen with one or multiple of the following routes/modes: direct/indirect contact, vector-borne, airborne or fecal-oral. The transmission occurs from an infected individual(s) to susceptible one(s) (3). The effects may be felt only locally, in the form of a small outbreak, or globally, in the case of a pandemic. When infectious agents spread exponentially and without any intervention, the results can be detrimental. Governments have multiple means to disrupt the transmission, like social distancing, disinfection, lockdowns, and vaccination. Specifically, a vaccine may influence the rate of transmission by reducing the number of susceptible individuals within a population. Depending on the vaccine’s effectiveness against the infection, its influence may be stronger or weaker. In case of a breakthrough infection (which is the infection of a vaccinated individual), a vaccine still teaches the immune system how to get rid of a pathogen more effectively. Furthermore, it can help slow down the replication of the infectious agent and, consequently, its spread to secondary hosts (4).
It is true that no initial clinical trials tested the direct influence of their vaccine on the rate of transmission of SARS-CoV-2 (5). The EMA recommendations were the basis for the establishment of the primary endpoints. Namely, the infection rate was used as the main determinant of the vaccine effectiveness:
“The primary endpoint in pivotal vaccine efficacy trials should be laboratory-confirmed COVID-19 disease of any severity. The primary analysis of efficacy should be restricted to study participants who were seronegative for the virus at baseline as it is important to show that the vaccine protects subjects not likely to have been exposed to the virus before.” (EMA considerations on COVID-19 vaccine approval (2)).
Based on the recommendations, the Pfizer/BioNTech clinical scientists pre-specified the evaluation of the vaccine in the trial protocol in the following manner (p. 19):
“To evaluate the efficacy of prophylactic BNT162b2 against confirmed COVID-19 occurring from 7 days after the second dose in participants without evidence of infection before vaccination” (5).
Importantly, several analyses of how the vaccine interrupts viral transmission have been published since the vaccines were widely available (6, 7, 8). They have confirmed that the vaccines have had a positive impact in reducing the spread of SARS-CoV-2.
In summary, it is true that the reduction of transmission of SARS-CoV-2 was not evaluated in the initial clinical trials. Such primary endpoints are not typical in vaccine approval nor were they recommended by regulatory agencies (read here our previous article on clinical trials). The confusion might have stemmed from miscommunication and not from any form of fraud or lack of transparency. The manufacturer followed standard recommendations and the information was available already in 2020. Indirectly, a possibility of transmission reduction can be inferred from the reduction of infections in clinical trials. In fact, there is a lower possibility that an immunized population (due to vaccination or infection) will efficiently transmit SARS-CoV-2. Furthermore, reduction of transmission was directly confirmed in the post-marketing studies (6, 7, 8).
References:
- https://multimedia.europarl.europa.eu/en/video/lessons-learned-and-recommendations-for-the-future-extracts-from-the-exchange-of-views-ep-special-committee-on-the-covid-19-pandemic_I231213.
- Ema Considerations on Covid-19 Vaccine Approval. https://www.ema.europa.eu/en/documents/other/ema-considerations-covid-19-vaccine-approval_en.pdf.
- Lahariya, C. “Vaccine Epidemiology: A Review.” J Family Med Prim Care 5, no. 1 (Jan-Mar 2016): 7-15. https://doi.org/10.4103/2249-4863.184616. https://www.ncbi.nlm.nih.gov/pubmed/27453836
- Leung, N. H. L. “Transmissibility and Transmission of Respiratory Viruses.” [In English]. Nature Reviews Microbiology 19, no. 8 (Aug 2021): 528-45. https://doi.org/10.1038/s41579-021-00535-6. <Go to ISI>://WOS:000631482900001.
- Thomas, S. J., E. D. Moreira, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, J. L. Perez, et al. “Safety and Efficacy of the Bnt162b2 Mrna Covid-19 Vaccine through 6 Months.” [In English]. New England Journal of Medicine (Sep 15 2021). https://doi.org/10.1056/NEJMoa2110345. <Go to ISI>://WOS:000696036700001.
- Layan, M., M. Gilboa, T. Gonen, M. Goldenfeld, L. Meltzer, A. Andronico, N. Hoze, S. Cauchemez, and G. Regev-Yochay. “Impact of Bnt162b2 Vaccination and Isolation on Sars-Cov-2 Transmission in Israeli Households: An Observational Study.” Am J Epidemiol 191, no. 7 (Jun 27 2022): 1224-34. https://doi.org/10.1093/aje/kwac042. https://www.ncbi.nlm.nih.gov/pubmed/35238329.
- Lyngse, F. P., K. Molbak, M. Denwood, L. E. Christiansen, C. H. Moller, M. Rasmussen, A. S. Cohen, et al. “Effect of Vaccination on Household Transmission of Sars-Cov-2 Delta Variant of Concern.” Nat Commun 13, no. 1 (Jun 30 2022): 3764. https://doi.org/10.1038/s41467-022-31494-y. https://www.ncbi.nlm.nih.gov/pubmed/35773247
- Shah, A. S. V., C. Gribben, J. Bishop, P. Hanlon, D. Caldwell, R. Wood, M. Reid, et al. “Effect of Vaccination on Transmission of Sars-Cov-2.” N Engl J Med 385, no. 18 (Oct 28 2021): 1718-20. https://doi.org/10.1056/NEJMc2106757. https://www.ncbi.nlm.nih.gov/pubmed/34496200.