COVID-19: Update on the Moderna Vaccine Trial (30 May 2020)
To date, I’ve written eight COVID-themed posts, each of which focuses on one or more aspects of the SARS-CoV-2 virus or the disease it causes (i.e. COVID-19). Here, I revisit the topic of vaccines — specifically, the NIAID-Moderna candidate vaccine, which I discussed in my 23 March post. The vaccine, called “mRNA-1273”, is the result of a collaboration between the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Disease (NIAID) and Moderna (a Cambridge, Massachusetts-based biotechnology company that is focused on drug discovery and development). The mRNA-1273 vaccine expresses a spike protein found on the surface of SARS-CoV-2 which mediates the attachment of the virus to host cell surface receptors and facilitates viral entry into the host cell. By using these proteins in a vaccine, Moderna scientists hope to prime the immune system, so that should the proteins be encountered again (i.e. during infection with SARS-CoV-2), they are recognized by the immune system, neutralized, and cleared from circulation. The effectiveness of this approach is predicated on whether the antibodies formed are, in fact, neutralizing antibodies, as there are some infections in which antibodies formed against the pathogen do not necessarily confer protection from reinfection (e.g. HIV and syphilis). Promisingly, in pre-clinical studies, vaccination with mRNA-1273 prevented viral replication in the lungs of mice challenged with SARS-CoV-2.
The NIAID-Moderna candidate vaccine Phase 1 clinical trial began on 16 March at Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle. Recall that a Phase 1 trial (formerly referred to as a “first-in-human” study) involves testing the vaccine in a small number of volunteers to assess safety, side effects, optimal dosing and formulation. Phase 1 trials do not assess efficacy, which is instead evaluated in subsequent phases. In this Phase 1 trial, 45 study participants aged 18–55 years, were grouped into three cohorts, with each cohort receiving one or two doses of the vaccine at 25 µg, 100 µg, and 250 µg. According to data released by Moderna on 18 May, all study participants seroconverted (That is to say, had measurable antibody against the protein) by day 15, after a single dose. Moreover, by day 43 (two weeks following the second dose, at the 25 µg dose for one of the cohorts), the antibody titer was comparable to that found in convalescent sera (i.e. the sera of individuals who have recovered from COVID-19); and at day 43, the antibody titers among the 100 µg cohort exceeded levels seen in convalescent sera. Additionally, plaque reduction neutralization assays conducted for the first four participants in the 25 µg as well as the 100 µg cohorts, neutralized SARS-CoV-2 in vitro. According to Moderna, the vaccine was safe and well tolerated, and adverse events were generally limited, non-urgent and transient. (https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-phase-1-data-its-mrna-vaccine)
Based on these interim data, Moderna plans on advancing the mRNA-1273 candidate vaccine to a Phase 2 study looking at 50 µg and 100 µg dosing cohorts. Phase 2 studies consist of larger groups (50–300 people) and, in addition to safety, assess clinical efficacy. On 12 May, the FDA granted mRNA-1273 Fast Track designation, and assuming the Phase 2 study is successful (and only about 31% of phase 2 studies are successful), Moderna plans on advancing to a Phase 3 study in July, according to Chief Executive Officer Stéphane Bancel. Phase 3 studies are large scale trials (i.e. 300–3000 plus individuals) and considered to be the definitive assessment (other than post-marketing surveillance) of a drug or vaccine’s safety and effectiveness.
A search of federally funded clinical trials conducted on 26 May and using the search terms “COVID” or “SARS-CoV-2” produced 1,717 results, of which 993 are clinical trials. (https://clinicaltrials.gov/ct2/results?cond=covid&age_v=&gndr=&type=Intr&rslt=&Search=Apply) A similar search of the World Health Organization’s International Clinical Trials Registry Platform produced 1,303 additional studies not found on the ClinicalTrials.gov website. Both of these are comprehensive lists of pre-clinical and clinical studies of therapeutics and preventatives, as well as studies of the virus itself and of infected patients. A list of solely the current COVID-19 vaccine candidates (numbering 25 on 26 May) can be found at https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker. Of these vaccine candidates, eight are in Phase 1 or 2 trials. In addition to Moderna’s mRNA-1273 vaccine, these include: 1) a Bacillus Calmette-Guerin (BCG) live-attenuated vaccine (Although the BCG vaccine is designed to prevent tuberculosis, it has been used to boost the immune response against other conditions such as transitional cell carcinoma of the bladder); 2) a recombinant novel coronavirus vaccine that incorporates the adenovirus type 5 vector; 3) a recombinant novel coronavirus vaccine that incorporates a chimpanzee adenovirus vaccine vector called AZD1222; 4) an intradermal DNA vaccine called INO-4800; 5) four mRNA-based vaccines (other than Moderna’s mRNA-1273); 6) a Chinese inactivated COVID-19 vaccine candidate; and 7) a formalin-inactivated, alum-adjuvanted candidate vaccine. According to the website, this list is updated weekly.
Before concluding this post, it’s worth mentioning the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative of the National Institutes of Health (NIH). Confronted with myriad pre-clinical and clinical studies, all of which are competing for volunteer participants, and most of which will not advance to market, ACTIV intends to bring the NIH together with other agencies in the Department of Health and Human Services as well as the Department of Defense (DOD), Department of Veterans Affairs (VA), the European Medicines Agency (EMA), and representatives from academia, philanthropic organizations, and more than 15 bio-pharmaceutical companies in order to: 1) develop a collaborative, streamlined forum to identify pre-clinical treatments; 2) accelerate clinical testing of the most promising vaccines and treatments; 3) improve clinical trial capacity and effectiveness; and 4) accelerate the evaluation of vaccine candidates to enable rapid authorization or approval. In short, ACTIV aims to “establish a collaborative framework for prioritizing vaccine and therapeutic candidates, to streamline clinical trials and tap into existing clinical trial networks, and to coordinate regulatory processes and leverage assets among all partners”. (https://www.nih.gov/research-training/medical-research-initiatives/activ)
To date, I’ve given a general overview of coronaviruses, including SARS-CoV-2 (1 and 13 March 2020), a review of investigational therapeutics and vaccines currently being studied (23 March and 6 April), a discussion about the role of masks in providing protection from COVID-19 (6 April 2020), as well as a discussion of the virus’ transmissibility, viability on inanimate surfaces, and associated case fatality rate (14 April 2020), a discussion of SARS-CoV-2 antibodies and the potential role of antibody testing (20 April 2020), a brief review of microbiocidal agents, with a focus on virucidal agents (29 April 2020), and a discussion about some of the distinctive clinical features of critically ill COVID-19 patients and the challenges posed in their medical management (14 May); and in this, my ninth COVID-19-themed post, I revisited the research being done on vaccines against SARS-CoV-2 with an update on Moderna’s mRNA-1273 vaccine. As with my prior posts, my only agenda is to inform you, the reader, and whenever possible, to assuage the anxiety surrounding the pandemic.
Until my next update — regards.
Michael Zapor, MD, PhD, CTropMed, FACP, FIDSA
(30 May 2020)
