COVID-19: The Russian COVID-19 Vaccine Candidate (6 September 2020)
In several prior posts, I describe the research underway to produce a vaccine against SARS-CoV-2, the virus that causes COVID-19 (1,2). According to the World Health Organization (WHO), there were 175 COVID-19 vaccines being researched worldwide as of 3 September 2020 (3). Of these, 34 are in clinical trials (i.e. being tested in human volunteers) with the rest still pre-clinical. One vaccine candidate that is garnering attention in the popular press is a Russian construct, and the subject of this post.
Recognizing that most people do not have a background in vaccinology, I thought it might be helpful first to make a few general comments about vaccine development. The basic principle of any vaccine is to present some pathogen or part of a pathogen to the immune system so that should the immune system encounter it again (i.e. by infection), it “remembers” (anthropomorphically speaking) the pathogen and quickly responds (This is referred to as an “anamnestic” response). The challenge is to produce a vaccine that is immunogenic (i.e. immune stimulating) enough to trigger a robust protective response without being so reactogenic that the vaccine makes the vaccinated individual as sick as does infection with the “wild-type” (i.e. naturally occurring) pathogen. The approach to making vaccines varies, but basic methods include the use of: 1) live, attenuated (i.e. weakened) organisms; some examples include varicella (chickenpox), measles/mumps/rubella, influenza, rotavirus, oral polio, and zoster (shingles); 2) inactivated (i.e. killed) organisms, such as the intramuscular polio vaccine, hepatitis A, and rabies; 3) toxoid (i.e. inactivated toxin), including diphtheria and tetanus; and 4) subunit/conjugate (i.e. recombinant) constructs, such as hepatitis B, intramuscular influenza, Haemophilus influenza type b, Pertussis, pneumococcus, meningococcus, and Human papillomavirus. In the 1990s, a new approach emerged utilizing the nucleic acid (i.e. DNA or RNA) of a pathogen as a vaccine. The principle here is that once the nucleic acid is injected into a person, its genes will be expressed to make protein that will trigger an immune response. This is the basis of a U.S. vaccine candidate that is currently being tested — a product of 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). I describe this particular vaccine in a prior post (1) as well as in a subsequent update (2).
Once a vaccine candidate has demonstrated safety and efficacy in an animal model, it advances to human clinical trials. This entails a phased approach that is required by the Food and Drug Administration (or the European Medicines Agency) before a vaccine (or drug) is granted approval for use. Although the approach sometimes varies, it generally consists of four phases (I-IV). Briefly, Phase I trials, also known as “first-in-human studies”, typically consist of 20–100 human volunteers and are designed to test the safety, side effects, and optimal dosing of a vaccine. Phase II trials involve 50–300 volunteers and assess efficacy as well as an ongoing evaluation of safety (Sometimes Phase II trials are further divided into Phase IIa and Phase IIb). If a vaccine performs satisfactorily in a Phase II clinical trial, it advances to a Phase III trial, which is a randomized controlled multicenter study (the “Gold standard”) involving hundreds to thousands of volunteers and is intended to assess safety and efficacy (4). Generally speaking, about 70 percent of vaccine candidates advance from Phase I to Phase II, 58 percent advance from Phase II to Phase III, and 75 percent in Phase III studies get FDA approval. This translates to about one out of four vaccine candidates in Phase I trials eventually getting FDA approval (5). The probability of success ranges, with industry-sponsored vaccine candidates being more likely than others to get FDA approval (6). Additionally, once a vaccine is granted FDA approval, post marketing studies are conducted (Phase IV). This is typically when very infrequent side effects become apparent.
On 4 September 2020, researchers funded by the Ministry of Health of the Russian Federation published online the results of two Phase I and Phase II COVID-19 vaccine trials (7). The vaccine consists of two recombinant adenovirus vectors (rAd5 and rAd26) carrying the gene for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). Adenoviruses were first isolated in 1953 from adenoid tissue (hence their name), and there are presently 51 distinct serotypes causing respiratory, ocular, and gastrointestinal illnesses (8). Adenovirus vectors offer several advantages including broad tissue tropism, a well-characterized genome, ease of genetic manipulation, inherent adjuvant properties, and an ability to induce robust transgene-specific T cell and antibody responses (9). Moreover, although their DNA is transcribed (i.e. used as a template to synthesize mRNA) in the host cell nucleus, it is neither replicated in the host cell nor incorporated into the host genome. Vaccinologists capitalize on this by cloning genes of interest into the adenovirus, to be transcribed into mRNA, which is then translated into a protein that elicits the desired immune response (in this case, against the SARS-CoV-2 spike protein). To date, several human clinical trials have been conducted using adenovirus vector-based vaccines against infectious diseases including Ebola virus, Zika virus, influenza viruses, Human Immunodeficiency Virus (HIV), Mycobacterium tuberculosis, and malaria. Additionally, adenovirus vectors are studied for prevention of other diseases as well, including certain cancers (e.g. pancreas, prostate, bladder, colon, non-small cell lung, renal, brain, and hepatocellular) and for gene replacement therapy. The use of adenovirus vectors is not without challenges, as evidenced by the 1999 death of eighteen-year-old Jesse Gelsinger in a University of Pennsylvania study in which an adenovirus vector was being studied for the replacement of a defective ornithine transcarbamylase gene (9). Some of these challenges include pre-existing immunity to adenoviruses, the potential for oncogenesis, a concern for reacquisition of the ability to replicate, etc., each of which has been tackled at some point (10).
There were two arms (cohorts) in the Russian study, each consisting of thirty-eight volunteers. The volunteers in one arm received a frozen formulation of the vaccine (Gam-COVID-Vac) and the volunteers in the other arm received a lyophilized (i.e. cryodesiccated) formulation. Within each of the two arms, nine study participants received rAd5-S, nine received rAd26-S, and twenty received rAd26-S on day 0 and rAd5-S on day 21. The most common adverse events were pain at the injection site in 44 participants (58%), hyperthermia in 38 (50%), headache in 32 (42%), asthenia (fatigue) in 21 (28%), and myalgia and arthralgia (muscle pain and joint pain, respectively) in 18 (24%). None of the side effects were considered by the researchers to be severe. When examined on day 42, all study participants had seroconverted (i.e. had measurable antibody against the spike protein). Moreover, the titers of neutralizing antibody were comparable to those seen in individuals convalescing from COVID-19. Additionally, cell-mediated immune responses were detected in all individuals at day 28, with a proliferation of CD4 and CD8 lymphocytes.
Although the results of the Russian vaccine trials are encouraging, the decision to register the vaccine and to distribute it to high-risk groups before conducting Phase III trials, as well as plans for mass vaccinations next month, elicited widespread criticism of the Russian Ministry of Health for rushing the vaccine’s release (a sentiment which may have been reinforced by the choice of the name “Sputnik V” for the Phase 1/2 trials, an obvious reference to Russia’s 1957 first-in-space satellite, Sputnik I). Nonetheless, researchers at the Gamaleya National Research Centre for Epidemiology and Microbiology in Russia are planning for a Phase 3 trial, which is expected to involve 40,000 volunteers. The Russian decision to fast track its vaccine evinces the conflicting pressure to deal with a pandemic quickly and decisively and at the same time, thoroughly vet the vaccine for both safety and efficacy. In this regard, they are not alone. The reader may recall that three months ago, China also curtailed Phase III testing and began inoculating members of its military with an experimental recombinant adenoviral COVID-19 vaccine, and subsequently expanded vaccination to high risk groups (11). In this country, several vaccine candidates are currently in Phase III trials, including those of Pfizer and Moderna (about which I have posted previously). Of note, Moderna recently slowed down enrollment in its trial to ensure better representation of minority participants who, once infected, are at greater risk for severe COVID-19 disease (12).
As with my prior COVID-19-themed posts, my intention here is not to politicize, sensationalize, or trivialize the pandemic, but only to provide information and thoughtful commentary.
Until my next update — regards.
Michael Zapor, MD, PhD, CTropMed, FACP, FIDSA
(6 September 2020)
To read this and my other COVID-19 posts on Medium.com, please see: https://medium.com/@michaelzapor. For best results, use Microsoft Edge or Google Chrome (Only a handful of the posts can be seen with Internet Explorer).
References
1. https://medium.com/@michaelzapor/covid-19-therapeutics-and-vaccines-23-march-2020-abc59b788650
3. file://r04.med.va.gov/v05/MWV/Users/VHAMWVZAPORM/Desktop/novel-coronavirus-landscape-covid-19-(4).pdf (Accessed 4 SEP 2020)
4. https://en.wikipedia.org/wiki/Phases_of_clinical_research#Phase_IV
5. https://www.acsh.org/news/2020/06/11/clinical-trial-success-rates-phase-and-therapeutic-area-14845
6. Lo A, Siah K, Wong C (14 May 2020). “Estimating probabilities of success of vaccine and other anti-infective therapeutic development programs”. Harvard Data Science Review. MIT Press (Special Issue 1 — COVID-19). doi:10.1162/99608f92.e0c150e8
7. Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5
vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomized phase 1/2 studies from Russia. The Lancet. https://doi.org/10.1016/S0140-6736(20)31866-3 (September 4, 2020)
8. https://www.genetherapynet.com/viral-vector/adenoviruses.html (Accessed 6 SEP 2020)
9. https://www.sciencehistory.org/distillations/the-death-of-jesse-gelsinger-20-years-later (Accessed 6 SEP 2020)
10. https://www.intechopen.com/books/adenoviruses/adenoviral-vector-based-vaccines-and-gene-therapies-current-status-and-future-prospects (Accessed 6 SEP 2020)
11. https://www.cbc.ca/news/health/covid-vaccine-approved-military-use-china-1.5630947 (Accessed 6 SEP 2020)
12. https://www.cnbc.com/2020/09/04/moderna-slows-coronavirus-vaccine-trial-t-to-ensure-minority-representation-ceo-says.html (Accessed 6 SEP 2020)
