COVID-19: Synopsis of the available and likely soon to be available COVID-19 vaccines (9 February 2021)
In several prior posts, I describe the conventional sequence of vaccine development (i.e. pre-clinical research, Phase 1, 2, and 3 clinical trials, and post-marketing surveillance), as well as the research then underway to produce a vaccine against SARS-CoV-2, the virus that causes COVID-19 (1,2). Subsequent to my last post, two mRNA vaccines, Moderna’s COVID-19 vaccine and Pfizer-BioNTech’s COVID-19 vaccine, received FDA emergency use authorization (EUA) and are being mass produced and widely distributed throughout the United States; and as of 4 February, 27,905,197 people have received their first dose of the vaccine, and 6,926,050 have received the full two doses (3). This translates to 8.5% of Americans having received one dose and 2.1% having received both doses. Additionally, on 4 February, Johnson & Johnson submitted an EUA request to the FDA for its adenovirus vector COVID-19 vaccine, and the FDA expects to meet on 26 February to formally review their data (4).
Although both Moderna and Pfizer intend to scale up production of their vaccines, with Moderna projecting 600 million to 1 billion doses this year (5) and Pfizer projecting 50 million doses globally this year and up to 1.3 billion next year (6), vaccine is currently unavailable to most Americans and is being distributed according to recommendations from the CDC and the Advisory Committee on Immunization Practices (7,8). Notwithstanding, as of 4 February 2021, there were 7,955 COVID-19-related studies registered with the World Health Organization’s International Clinical Trials Registry Platform (9). Of these, 192 are clinical trials of vaccine candidates (10). These vaccines run the gamut from non-replicating viral vectors (#48), protein subunit vaccines (#45), inactivated virus vaccines (#33), RNA-based vaccines (#28), DNA-based vaccines (#17), replicating viral vectors (#6), non-replicating, antigen-presenting viral vectors (#5), live attenuated viruses (#1), virus-like particles (#4), and others (#5). These 192 vaccine candidates are in various stages of study, with 55 in Phase 1 trials, 61 in Phase 1/Phase2 trials, 25 in Phase 2 trials, 11 in Phase 2/Phase 3 trials, and 35 vaccine candidates in Phase 3 trials. Of these, results have been published to date for eight vaccine candidates including three adenovirus vector vaccines (Johnson & Johnson/BARDA, CanSino Biologics, U.K. Ministry of Health/Oxford University/BARDA), three inactivated virus candidates (Sinovac, China Ministry of Science and Technology, Chinese National program on Key Research/Chinese National Mega Products/Beijing Science and Technology plan), and two recombinant vaccine candidates (Novavax/CEPI/Department of Defense, Russian Ministry of Health) (11).
In this post, I briefly describe the vaccine candidates for which data has been published. I am not including information here on the two mRNA vaccines with FDA EUA (i.e. Moderna and Pfizer), as I have written about them previously.
Johnson & Johnson (Ad26.COV2.S)
The Janssen Pharmaceutical Companies of Johnson & Johnson Ad26.COV2.S COVID-19 vaccine is a single dose vaccine using a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein. The vaccine’s development was spurred by an expanded collaboration between Janssen and the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response (ASPR) at the U.S. Department of Health & Human Services. Additionally, the Ad26.COV2.S vaccine employs the same technology that Janssen used in the development of its Ebola vaccine and investigational HIV, RSV, and Zika vaccine candidates. Interim Results of a Phase 1–2a trial of Ad26.COV2.S were published in the New England Journal of Medicine (12). In this study, neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose and reached 100% by day 57 with a further increase in titers. A second dose provided an increase in the titer by a factor of 2.6 to 2.9. Moreover, on day 14 robust cellular responses consisting chiefly of type 1 helper T cells and, to a lesser extent, CD8+ T-cells were seen in the majority of study participants. (Of note, the first author of this study, Jerald Sadoff, M.D., was my boss when I first arrived at the Walter Reed Army Institute of Research in 1991.) An interim analysis (called ENSEMBLE) of an ongoing randomized, double-blind, placebo-controlled phase 3 clinical trial of 43,783 study volunteers showed the Ad26.COV2.S vaccine to be 66% effective in preventing moderate to severe COVID-19 at 28 days after vaccination and 85% effective in preventing hospitalization and death (13). A parallel study (called the ENSEMBLE 2 trial) will involve the administration of two doses of the vaccine candidate spaced two months apart to see if a second dose provides greater or longer lasting protection (14). Provided Johnson & Johnson is granted EUA when the FDA convenes on 26 February, the company plans to deliver 100 million doses in the U.S. and more than one billion doses globally through 2021.
Convidicea Vaccine (Ad5-nCoV)
The Convidicea Vaccine (Ad5-nCoV), a product of China’s CanSino Biologics, is a replication-defective adenovirus type 5 engineered to express the SARS-CoV-2 spike protein (a protein similarly expressed by both the Moderna and Pfizer mRNA vaccines). A study of 108 volunteers published in The Lancet found the Ad5 vectored COVID-19 vaccine to be tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination (15). The most commonly reported adverse reactions were pain at the injection site (54%), fever (46%), fatigue (44%), headache (39%), and generalized myalgia (17%). On 29 June 2020, China’s military received permission to vaccinate soldiers, and a randomized, double-blind, placebo-controlled, phase 2 trial of 508 individuals also published in The Lancet found the vaccine to be both safe and immunogenic after a single administration (16). On 11 August, China granted its first COVID-19 vaccine patent and in September 2020, the Russian vaccine manufacturer Petrovax was granted exclusive rights to provide the vaccine in Russia and its eleven Commonwealth Independent States. As of 4 February 2021, CanSino had also made deals to test or distribute the Ad5-nCoV vaccine in Malaysia, Mexico, and Chile (17,18,19). Trials of the Ad5-nCoV vaccine are ongoing and include studies of safety and immunogenicity (Clinical Trials NCT04540419, NCT04526990, and NCT04566770) as well as the efficacy of a boosted regimen (Clinical Trial NCT04568811).
Oxford-AstraZeneca COVID-19 Vaccine (AZD1222)
The Oxford-AstraZeneca COVID-19 Vaccine (AZD1222 also known as ChAdOx1 nCoV-19 vaccine) is a replication-deficient simian adenovirus vector containing the full‐length coding sequence of SARS-CoV-2 spike protein along with a tissue plasminogen activator leader sequence (20). It represents a collaboration between Oxford University and AstraZeneca and has been in clinical trials involving 23,848 participants in Brazil, South Africa, and the United Kingdom. In an interim primary efficacy analysis of 11,636 participants, vaccine efficacy was dose dependent (range 62–90%) with efficacy across all cohorts being 70.4% (21). Interestingly, efficacy seemed to be higher in a cohort inadvertently given a reduced 1st dose followed by a standard 2nd dose. Safety data was available from 74,341 person-months of follow-up after first dose (median 3.4 months) and 29,060 person-months of follow-up after two doses (median 2 months). Serious adverse events occurred in 168 participants; 79 of these were in the vaccinated group, and 89 were in the placebo group. The AZD1222 vaccine was approved for use on 30 December 2020 and on 29 January 2021, the European Medicines Agency (EMA) recommended granting a conditional marketing authorization for AZD1222 in people 18 years of age or older (22). The vaccine has also been approved by numerous other countries. An advantage conferred by the AZD1222 vaccine is that it is stable for storage under refrigeration (i.e. 2–8o C), making it more practical for use in places such as low-income countries, where maintaining a cold chain is problematic. The vaccine has not yet been granted emergency use authorization in the United States.
Sinovac (CoronaVac)
The Coronavac vaccine (formerly called PiCoVacc) is a more traditional vaccine construct consisting of inactivated SARS-CoV-2 virus with an aluminum hydroxide adjuvant (i.e. a substance added to a vaccine which enhances the immune response to an antigen). The vaccine’s sponsor is Sinovac Biotech Ltd., a Chinese biopharmaceutical company; and the CoronaVac vaccine is the second approved for general use in China and one of four comprising China’s current COVID-19 vaccine portfolio. The vaccine was tested in a randomized, double-blind, placebo-controlled, phase 1/2 clinical trial involving two intramuscular injections of varying doses given on day 0 and day 28 (23). Between 22 May 2020 and 15 June 2020, 72 participants and 350 participants were enrolled in Phase 1 and Phase 2 studies, respectively. Seroconversion after the second dose ranged from 90.7% to 100%, depending on the dose administered; and adverse reactions were graded mild to moderate, with injection site pain being the commonest complaint (9%). CoronaVac has also been granted EUA by Indonesia, Turkey, Brazil, Chile, Colombia, Uruguay, and Laos. Interestingly, the reported efficacy of the vaccine in Phase 3 trials conducted in those countries varies from 50.65% in Brazil to 65.3% in Indonesia to 91.25% in Turkey. Sinovac is on track to produce over one billion doses, to include 10 million doses for COVAX, a World Health Organization-backed global vaccine-sharing initiative.
Wuhan Institute of Biological Products/Sinopharm (BBIBP-CorV)
BBIBP-CorV is an inactivated vaccine candidate developed at the Wuhan Institute of Biological Products that demonstrated protection against SARS-CoV-2 intratracheal challenge in rhesus macaques (24). In subsequent clinical studies, 192 and 448 study volunteers were enrolled in Phase 1 and Phase 2 trials, respectively. The vaccine-elicited dose-dependent neutralizing antibody titers on day 28 in all cohorts and all observed adverse reactions were graded mild or moderate in severity, with fever being the commonest complaint and dose dependent (1–8%). By November 2020, nearly one million people had received the vaccine through China’s emergency use program; and as of December 2020, BBIBP-CorV was in Phase 3 trials in Argentina, Bahrain, Egypt, Morocco, Pakistan, Peru, and the United Arab Emirates with over 60,000 participants (25). Like the AZD1222 vaccine candidate, BBIBP-CorV can be transported and stored at normal refrigeration temperatures, making it more practical for use in developing countries. In October 2020, Sinopharm announced that it may be able to produce more than one billion doses in 2021. Moreover, Dubai, Egypt, and Morocco all announced their intent to produce the vaccine locally under agreements with Sinopharm. However, widespread acceptance of the vaccine has been hindered by both a lack of publicly available data on safety and efficacy (26) as well as possible underreporting of adverse reactions (27).
Novavax/CEPI/Department of Defense (NVX-CoV2373)
NVX-CoV2373 is a COVID-19 vaccine candidate developed by Novavax and the Coalition for Epidemic Preparedness Innovations (CEPI). Described by the manufacturers as a “recombinant nanoparticle vaccine”, it consists of synthetic lipid nanoparticles each about 50 nanometers across and displaying up to 14 spike glycoproteins and Matrix-M1 adjuvant (28). The first human safety study of NVX-CoV2373 was conducted in Melbourne, Australia in May 2020 and the results were published in the New England Journal of Medicine in September 2020 (29). The study consisted of a randomized, placebo-controlled, phase 1–2 trial to evaluate the safety and immunogenicity of differing doses of the rSARS-CoV-2 vaccine with or without Matrix-M1 adjuvant. Two intramuscular doses were administered 21 days apart and the primary outcomes were reactogenicity, safety, and IgG antibody formation against the viral spike protein. No serious adverse events were noted. Reactogenicity was absent or mild in the majority of participants, more common with adjuvant, and of short duration (mean ≤2 days). Adverse reactions were similarly mild and there were no serious events. When examined at 35 days post-vaccination, study participants showed cellular (CD4+/Th1) and humoral responses that exceeded geometric mean responses seen in convalescent serum from symptomatic COVID-19 patients. However, interim results from a subsequent trial in South Africa showed the vaccine to be less effective against the 501.V2 variant of the virus, at around 50–60% (30). Notwithstanding, on 2 February 2021, Canada announced a tentative agreement for Novavax to produce millions of doses of NVX-CoV2373 in Montreal, which will make it the first COVID-19 vaccine to be produced in that country (31).
Gamaleya Research Institute of Epidemiology and Microbiology/Russian Ministry of Health (Gam-COVID-VacLyo/Gam-COVID-Vac [Sputnik V])
On 4 September 2020, researchers funded by the Ministry of Health of the Russian Federation published online the results of two Phase 1 and Phase 2 COVID-19 vaccine trials (32). The vaccine consists of two recombinant adenovirus vectors (rAd5 and rAd26) carrying the gene for the SARS-CoV-2 spike glycoprotein (rAd26-S and rAd5-S). There were two 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 were encouraging, the decision to register the vaccine and to distribute it to high-risk groups before conducting Phase 3 trials, as well as plans for mass vaccinations before such studies were completed, 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) (33). Nonetheless, mass distribution of the vaccine, both in Russia and several other countries, began in December 2020; and as of February 2021, twenty-one countries have granted Sputnik V EUA (34). In the meantime, a Phase 3 trial was initiated at the Skolkovo Innovation Center (the Moscow branch of Israel’s Hadassah Medical Center). The study is a randomized, double-blind, placebo-controlled, multi-center clinical trial involving 40,000 volunteers in Moscow, and is scheduled to run until May 2021 (35). An interim analysis of the data published in The Lancet on 2 February 2021 showed vaccine efficacy to be 91.6% and adverse events generally to be mild (grade 1) (36).
Epilogue
This curated review of COVID-19 vaccines and vaccine candidates is neither comprehensive nor exhaustive. Instead, my intent is simply to provide a concise synopsis of some of the currently available vaccines (minus the two mRNA vaccines about which I have previously written) as well as several vaccines that are in Phase 3 studies and likely to be approved under emergency use authorization in the near future. The speed with which these vaccine candidates are being produced is testimony to human ingenuity, collaboration, and a collective sense of urgency as well as the fact that antibodies formed against the virus appear to be somewhat protective (in contrast to some other pathogens such as the Human Immunodeficiency Virus [HIV] or Treponema pallidum [causative agent of syphilis]). The ultimate impact of these vaccines on halting the COVID-19 pandemic will be determined by a host of factors including duration of immunity, the role of reservoirs in reintroducing SARS-CoV-2, the emergence of vaccine-resistant variants, etc. With respect to the latter, I have written previously that RNA viruses such as coronaviruses are highly mutable (For a review of the topic, see the paper by Sanjuán and Domingo-Calap [37]). Indeed, three notable mutations: D641G (about which I have written elsewhere [38]), E484K, N501Y, as well as six notable variants: Lineage B.1.1.207, Lineage B.1.1.7 / Variant of Concern 202012/01, Cluster 5, 501.V2 variant, Lineage P.1, and Lineage B.1.429 / CAL.20C have been described to date for SARS-CoV-2 (39). The extent to which these and future variants will be able to evade vaccine-associated immunity has yet to be elucidated, but several vaccines have already demonstrated reduced efficacy against at least one, the South African variant, 501.V2, 20H/501Y.V2 (40,41). If this trend continues, it may be necessary to periodically reformulate the composition of vaccines and offer boosters that are effective against prevalent circulating strains (similar to our current approach towards seasonal influenza). Alternatively, a universal SARS-CoV-2 vaccine directed against the more highly conserved, less variable regions of the virus might obviate the need for such boosters. Of course, researchers have been seeking such a Holy Grail for influenza vaccines for quite some time and universal influenza vaccine candidates have yet to advance beyond the preclinical stage of research (42).
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
(9 February 2021)
To read this and my other COVID-19 posts on Medium.com, please see: https://medium.com/@michaelzapor
References
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