The phase I trial for INO-4800 began enrolling participants in April 2020 in Philadelphia, PA at the Perelman School of Medicine and at the Center for Pharmaceutical Research in Kansas City, MO. This trial examined two different doses administered in a two-dose regimen [@doi:10.1016/j.eclinm.2020.100689]. Among the 39 participants, only six AEs were reported and all were grade 1 [@doi:10.1016/j.eclinm.2020.100689]. Efficacy was evaluated based on blood samples collected pre- and post-vaccination, and all but three participants of 38 included in the analysis were found to have serum IgG binding titers to the spike protein after vaccination [@doi:10.1016/j.eclinm.2020.100689].
Results from the phase II trial were released as a preprint in May 2021 and reported findings based on administering INO-4800 to 401 adult volunteers at high risk of exposure to SARS-CoV-2 [@doi:10.1101/2021.05.07.21256652]. The phase II results supported that the vaccine was safe, with 1,446 treatment-related AEs observed across 281 participants, all but one of which were grade 1 or grade 2. The single grade 3 event was joint stiffness [@doi:10.1101/2021.05.07.21256652]. The rates of AEs in the placebo group were not reported. To assess the immunogenicity of INO-4800, pre- and post-vaccination blood samples were collected and evaluated for a humoral immune response to the spike protein, and the treatment group was identified to show significantly greater neutralizing activity than the placebo group [@doi:10.1101/2021.05.07.21256652].
The phase II/III trials are ongoing in several countries, including the United States, Mexico, India, and Colombia [@{url:https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Receives-U.S.-FDA-Authorization-to-Proceed-with-INNOVATE-Phase-3-Segment-for-its-COVID-19-Vaccine-Candidate-INO-4800-in-the-U.S/default.aspx}; @{url:https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Further-Expands-INNOVATE-Phase-3-Trial-for-COVID-19-DNA-Vaccine-Candidate-INO-4800-With-Regulatory-Authorization-from-India/default.aspx}; @{url:https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Expands-INNOVATE-Phase-3-for-INO-4800-its-DNA-Vaccine-Candidate-for-COVID-19-to-include-Colombia-following-Regulatory-Authorization/default.aspx}; @{url:https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Receives-Regulatory-Authorization-to-Conduct-Phase-3-Efficacy-Trial-of-its-COVID-19-DNA-Vaccine-Candidate-INO-4800-in-Mexico/default.aspx}]. Therefore, vaccine efficacy data from a large study population is not yet available.
Prior analyses of viral vector vaccines against human coronaviruses (HCoVs) had indicated that this approach showed potential for inducing an immune response, but little information was available about the effect on real-world immunity. In the first phase of development, a candidate ChAdOx1 nCoV-19 was evaluated through the immune challenge of two animal models, mice and rhesus macaques [@doi:10.1038/s41586-020-2608-y]. Animals in the treatment condition were observed to develop neutralizing antibodies specific to SARS-CoV-2 (both macaques and mice) and to show reduced clinical scores when exposed to SARS-CoV-2 (macaques) [@doi:10.1038/s41586-020-2608-y].
Next, a phase I/II trial was undertaken using a single-blind, randomized controlled design [@doi:10/gg5gwk]. ChAdOx1 nCoV-19 and a control, the meningococcal conjugate vaccine MenACWY, were administered intramuscularly to adults ages 18 to 55 at five sites within the United Kingdom (U.K.) at a 1:1 ratio (n=543 and n=534, respectively). All but ten participants received a single dose; this small group received a booster 28 days after their first dose of ChAdOx1 nCoV-19. Commonly reported local adverse reactions included mild-to-moderate pain and tenderness at the injection site over the course of seven days, while the most common systemic adverse reactions were fatigue and headache; some patients reported severe adverse systemic effects. The study also reported that many common reactions could be reduced through the administration of paracetamol (acetaminophen), and paracetamol was not found to reduce immunogenicity. Patients receiving the ChAdOx1 nCoV-19 vaccine developed antibodies to the SARS-CoV-2 spike protein that peaked by day 28, with these levels remaining stable until a second observation at day 56 except in the ten patients who received a booster dose at day 28, in whom they increased by day 56. Analysis of serum indicated that participants developed antibodies to both S and the RBD, and that 100% of them achieved neutralizing titers by day 28. By day 35, the neutralization titers of vaccinated patients was comparable to that observed with plasma from convalescents. This initial study therefore suggested that the vaccine was likely to confer protection against SARS-CoV-2, although analysis of its efficacy in preventing COVID-19 was not reported.
The primary outcome assessed was symptomatic, laboratory-confirmed COVID-19. There were 131 cases observed among the 11,636 participants eligible for the primary efficacy analysis, corresponding to an overall efficacy of 70.4% (30 out of 5,807 in the vaccine arm and 101 out of 5,829 in the control arm); the 95.8% CI was reported as 54.8 to 80.6. However, a higher efficacy was reported in the subgroup of patients who received a low-dose followed by a standard dose (90.0%, 95% CI 67.4 to 97·0). A total of ten cases of severe COVID-19 resulting in hospitalization were observed among trial participants, and all of these occurred in patients in the control arm of the study. In line with the previously reported safety profiling for this vaccine, serious adverse events were reported to be comparable across the two arms of the study, with only three events identified as potentially associated with the vaccine itself.
Additional data about the efficacy of this vaccine became available in a preprint released on March 2, 2021 [@doi:10.1101/2021.03.01.21252652]. This report provided data describing the efficacy of ChAdOx1 nCoV-19, along with Pfizer/BioNTech's BNT162b2, in the U.K. between December 8, 2020 and February 19, 2021 and specifically sought to evaluate the efficacy of the vaccine in the presence of a potentially more contagious variant of concern, B.1.1.7. All participants in this study were age 70 or older and the efficacy was estimated to increase from 60% at 28 days after vaccination to 73% at 35 days after vaccination, although the standard error also increased over this time. Therefore, preliminary results suggest that in a number of samples, this vaccine confers a high level of protection against SARS-CoV-2.
The vaccine Gam-COVID-Vac, nicknamed Sputnik V in reference to the space race and "V for vaccine", was developed by the Gamaleya National Center of Epidemiology and Microbiology in Moscow. The development of Sputnik V was financed by the Russian Direct Investment Fund (RDIF) [@doi:10/ft7j; @doi:10/ghs3sn]. The Sputnik V vaccines are available in both a lyophilized (Gam-COVID-Vac-Lyo) and frozen form (Gam-COVID-Vac), which are stored at 2-8°C and -18°C respectively [@doi:10/gg96hq]. The lyophilized vaccine is convenient for distribution and storage, particularly to remote or disadvantaged areas [@doi:10.3390/v13010054].
In the phase I/II trial study conducted between late June and early August 2020, 76 participants (18-60 years old) were split into two groups of 38 participants, which were non-randomized in two hospitals in Russia. In phase I, 9 patients received rAd26 and 9 patients received rAd5-S to assess safety over 28 days. In phase II, at least 5 days after the completion of phase I, 20 patients received a prime-boost vaccination of rAd26-S on day 0 and rAd5-S on day 2, which was administered intramuscularly. The phase I/II trial reported that both vaccines were deemed safe and well tolerated. The most common adverse events reported were mild, such as pain at the injection site (58%), hypothermia (50%), headaches (42%), fatigue (28%), and joint and muscle pain (24%). Seroconversion was observed in all participants three weeks post the second vaccination (day 42), and all participants produced antibodies to the SARS-CoV-2 glycoprotein. RBD-specific IgG levels were high in both the frozen and lyophilized versions of the vaccine (14,703 and 11,143 respectively), indicating a sufficient immune response to both. Three weeks post the second vaccination, the virus-neutralizing geometric mean antibody titers were 49.25 and 45.95 from the frozen and lyophilized vaccines, respectively. At 28 days, median cell proliferation of 1.3% CD4^+^ and 1.1% CD8^+^ were reported for the lyophilized vaccine and 2.5% CD4^+^ and 1.3% CD8^+^ for the vaccine stored frozen. These results indicated that both forms of Sputnik V appeared to be safe and induced a humoral and cellular response in human subjects [@doi:10/gg96hq], which may be robust enough to persist and not wane rapidly [@doi:10/ghx7xz].
In February 2021, the interim results of the phase III randomized, double-blind, placebo-controlled trial were published in The Lancet [@doi:10/ghxj4g]. The participants were randomly assigned to receive either a 0.5 mL/dose of vaccine or placebo, which was comprised of the vaccine buffer composition, that was delivered intramuscularly using the same prime-boost regimen as in the phase I/II trials. From September 7 to November 24, 19,866 participants completed the trial. Of the 14,964 participants who received the vaccine, 16 (0.1%) were confirmed to have COVID-19, whereas 62 of the 4,902 participants (1.3%) in the placebo group were confirmed to have COVID-19. Of these participants, no moderate or severe cases of COVID-19 were reported in the vaccine group, juxtaposed with 20 in the placebo group. However, only symptomatic individuals were confirmed for SARS-CoV-2 infection in this trial. Therefore, asymptomatic infections were not detected, thus potentially inflating the efficacy estimate. Overall, a vaccine efficacy of 91.6% (95% CI 85.6-95.2) was reported, where an efficacy of 91.8% was reported for those over 60 years old and 92.7% for those who were 51-60 years old. Indeed, 14 days after the first dose, 87.6% efficacy was achieved and the immunity required to prevent disease occurred within 18 days of vaccination.
Based on these results, scientists are investigating the potential for a single dose regimen of the rAd26-S sputnik V vaccine [@doi:10.1136/bmj.n309]. By the end of the trial, 7,485 participants reported adverse events, of which 94% were grade I. Of the 68 participants who experienced serious adverse events during the trial, 45 from the vaccine group and 23 from the placebo groups, none were reported to be associated with the vaccination. Likewise, 4 deaths occurred during the trial period that were not related to the vaccine [@doi:10/ghxj4g]. The interim findings of the phase III trial indicate that the Sputnik V vaccine regimen appears to be safe with 91.6% efficacy. Gamaleya had intended to reach a total of 40,000 participants for the completion of their phase III trial. However, the trial has stopped enrolling participants and the numbers have been cut to 31,000 as many individuals in the placebo group dropped out of the study to obtain the vaccine [@url:https://apnews.com/article/coronavirus-pandemic-russia-163068f551e080939b982389b576320a]. Other trials involving Sputnik V are currently underway in Belarus, India, the United Arab Emirates, and Venezuela [@url:https://sputnikvaccine.com/about-vaccine].
Preliminary results of a trial of Argentinian healthcare workers in Buenos Aires who were vaccinated with the Sputnik V rAd26-R vector-based vaccine seems to support the short term safety of the first vaccination [@doi:10.1101/2021.02.03.21251071]. Of the 707 vaccinated healthcare workers, 71.3% of the 96.6% of respondents reported at least one adverse event attributed to the vaccine. Of these individuals, 68% experienced joint and muscle pain, 54% had injection site pain, 11% reported redness and swelling, 40% had a fever, and 5% reported diarrhea. Only 5% of the vaccinated participants experienced serious adverse events that required medical attention, of which one was monitored as an inpatient.
Additionally, an independent assessment of Sputnik V in a phase II clinical trial in India found the vaccine to be effective, but the data is not yet publicly available [@url:https://www.reuters.com/article/health-coronavirus-india-vaccine-idUSL4N2JM2XA]. On December 21, 2020, Gamaleya, AstraZeneca, R-Pharm, and the Russian Direct Investment Fund agreed to assess the safety and immunogenicity of the combined use of components of the AstraZeneca and University of Oxford AZD1222 (ChAdOx1) vaccine and the rAd26-S component of the Sputnik V vaccine in clinical trials [@url:https://www.prnewswire.com/ae/news-releases/rdif-the-gamaleya-national-center-astrazeneca-and-r-pharm-sign-an-agreement-to-cooperate-on-covid-19-vaccine-development-301196874.html]. This agreement hopes to establish scientific and business relations between the entities with an aim to co-develop a vaccine providing long-term immunization. The trial, which will begin enrollment soon, will include 100 participants in a phase II open-label study and is hoped to be complete within 6 months. Participants will first receive an intramuscular dose of AZD1222 on day 1, followed by a dose of rAd26 on day 29 and be monitored from day 1 for 180 days in total. The primary outcomes measured will include incidence of serious adverse events post first dose until the end of the study. Secondary outcome measures will include incidence of local and systemic adverse events 7 days post each dose, a time course of antibody responses for the Spike protein and the presence of anti-SARS-CoV-2 neutralizing antibodies [@clinicaltrials:NCT04686773].
Overall, there is hesitancy surrounding the management of the Sputnik V vaccine approval process and concerns over whether the efficacy data may be inflated due to a lack of asymptomatic testing within the trial. However, the interim results of the phase III study were promising and further trials are underway, which will likely shed light on the overall efficacy and safety of the Sputnik V vaccine regimen. There may be some advantage to the Sputnik V approach including the favorable storage conditions afforded by choice between a frozen and lyophilized vaccine. Furthermore, the producers of Gam-COVID-Vac state that they can produce the vaccine at a cost of less than $10 per dose or less than $20 per patient [@url:https://sputnikvaccine.com].
The Johnson and Johnson (J&J) vaccine developed by Janssen Pharmaceuticals, Inc., a subsidiary of J&J, was conducted in collaboration with and funded by “Operation Warp Speed” [@url:https://www.gao.gov/products/gao-21-319; @url:https://www.jnj.com/johnson-johnson-announces-a-lead-vaccine-candidate-for-covid-19-landmark-new-partnership-with-u-s-department-of-health-human-services-and-commitment-to-supply-one-billion-vaccines-worldwide-for-emergency-pandemic-use; @doi:10.1056/NEJMoa2034201;@doi:10.1038/s41541-020-00243-x]. The vaccine was developed using Janssen’s AdVac^®^ and PER.C6 platforms that were previously utilized to develop the European Commission-approved Ebola vaccine (Ad26 ZEBOV and MVN-BN-Filo) and their Zika, respiratory syncytial virus, and human immunodeficiency virus investigational vaccine candidates [@url:https://www.jnj.com/johnson-johnson-initiates-pivotal-global-phase-3-clinical-trial-of-janssens-covid-19-vaccine-candidate].
The development of a single-dose vaccine was desired by J&J from the outset, with global deployment being a key priority [@doi:10.1038/s41586-020-2607-z]. Using their AdVac^®^ technology, the vaccine can remain stable for up to two years between -15 and -25℃ and at least three months at 2 to 8℃ [@url:https://www.jnj.com/johnson-johnson-initiates-pivotal-global-phase-3-clinical-trial-of-janssens-covid-19-vaccine-candidate]. This allows the vaccine to be distributed easily without the requirement for very low temperature storage, unlike many of the other COVID-19 vaccine candidates. J&J screened numerous potential vaccine candidates in vitro and in animal models using varying different designs of the S protein, heterologous signal peptides, and prefusion-stabilizing substitutions [@doi:10.1038/s41541-020-00243-x]. A select few candidates were further investigated as a single dose regimen in Syrian golden hamsters, a single dose regimen in rhesus macaques, and a single- and two-dose regimen in both adult and aged rhesus macaques [@doi:10.1038/s41541-020-00243-x; @doi:10.1038/s41586-020-2607-z; @doi:10.1038/s41591-020-1070-6; @doi:10.1101/2020.11.17.368258]. A SARS-CoV-2 challenge study in rhesus macaques showed that vaccine doses as low as 2 x 10^9^ viral particles/mL was sufficient to induce strong protection in bronchoalveolar lavage but that doses higher than 1.125 x 10^10^ were required to close achieve close to complete protection in nasal swabs [@doi:10.1101/2021.01.27.428380]. Indeed, six months post-immunization, levels of S-binding and neutralizing antibodies in rhesus macaques indicated that the JNJ-78436735 vaccine conferred durable protection against SARS-CoV-2 [@doi:10.1101/2021.01.30.428921].
Following selection of the JNJ-78436735 vaccine, J&J began phase I/IIa trials. The interim phase I/IIa data was placed on the medRxiv preprint server on September 25th, 2020 [@doi:10.1101/2020.09.23.20199604] and was later published in the New England Journal of Medicine on January 13th, 2021 [@doi:10.1056/NEJMoa2034201]. The phase I/IIa multi-center, randomized, placebo-controlled trial enrolled 402 healthy participants between 18-55 years old and a further 403 healthy older participants ≥ 65 years old [@doi:10.1056/NEJMoa2034201]. Patients were administered either a placebo, a low dose (5 x 10^10^ viral particles per mL), or a high dose (1 X 10^11^ viral particles per mL) intramuscularly as part of either a single- or two-dose regimen. All patients received injections 56 days apart, but participants in the single-dose condition received the placebo at the second appointment. Those who received only one dose of either vaccine received a placebo dose at their second vaccination visit. The primary endpoints of both the trial were safety and reactogenicity of each dose. Fatigue, headache, myalgia, and pain at the injection site were the most frequent solicited adverse events reported by participants. Although less common, particularly for those in the elderly cohort and those on the low dose regimen, the most frequent systemic adverse effect was fever. Overall, immunization was well tolerated, particularly at the lower dose concentration. In terms of reactogenicity, over 90% of those who received either the low or high dose demonstrated seroconversion in a neutralization assay using wild-type SARS-CoV-2, 29 days after immunization [@doi:10.1056/NEJMoa2034201]. Neutralizing geometric mean ratio of antibody titers (GMT) between 224-354 were detected regardless of age. By day 57, 100% of the 18-55 year old participants had neutralizing GMT (288-488), which remained stable until day 71. In the ≥ 65 years old cohort, the incidence of seroconversion for the low- and high-dose was 96% and 88% respectively by day 29.
GMTs for the low and high doses were slightly lower for participants ≥ 65 years old (196 and 127 respectively), potentially indicating slightly lower immunogenicity. Seroconversion of the S antibodies was detected in 99% of individuals between 18-55 years old for the low and high doses (GMTs 528 and 695 respectively), with similar findings reported for the ≥ 65 years old. Indeed, both dose concentrations also induced robust Th1 cytokine-producing S-specific CD4^+^ T cells and CD8^+^ T cell responses in both age groups. The findings of the phase I/IIa study supported further investigation of a single immunization using the low dose vaccine. Therefore, 25 patients were enrolled for a second randomized double-blind, placebo-controlled phase I clinical trial currently being conducted in Boston, Massachusetts for 2 years [@doi:10.1001/jama.2021.3645]. Participants received either a single dose followed by a placebo, or a double dose of either a low dose (5 x 10^10^ viral particles/mL) or a high dose (1 x 10^11^ viral particles/mL) vaccine administered intramuscularly on day 1 or day 57. Placebo-only recipients received a placebo dose on day 1 and 57. Interim analyses conducted on day 71 indicated that binding and neutralizing antibodies developed 8 days after administration in 90% and 25% of vaccine recipients, respectively. Binding and neutralizing antibodies were detected in 100% of vaccine recipients by day 57 after a single dose immunization. Spike-specific antibodies were highly prevalent (GMT 2432 to 5729) as were neutralizing antibodies (GMT 242 to 449) in the vaccinated groups. Indeed, CD4^+^ and CD8^+^ T-cell responses were also induced, which may provide additional protection, particularly if antibodies wane or poorly respond to infection [@doi:10.1038/s41586-020-03041-6].
On September 23rd, 2020, J&J launched its phase III trial ENSEMBLE and released the study protocol to the public [@url:https://www.jnj.com/johnson-johnson-initiates-pivotal-global-phase-3-clinical-trial-of-janssens-covid-19-vaccine-candidate; @clinicaltrials:NCT04505722]. The trial intended to enroll 60,000 volunteers to assess the safety and efficacy of the single vaccine dose versus placebo with primary endpoints of 14 and 28 days post-immunization [@url:https://www.jnj.com/johnson-johnson-initiates-pivotal-global-phase-3-clinical-trial-of-janssens-covid-19-vaccine-candidate]. The trial was conducted in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the U.S. The trial was paused briefly in October 2020 to investigate a “serious medical event”, but resumed shortly after [@url:https://www.jnj.com/our-company/johnson-johnson-prepares-to-resume-phase-3-ensemble-trial-of-its-janssen-covid-19-vaccine-candidate-in-the-us].
An interim analysis was reported via press release on January 29th, 2021 [@url:https://www.nih.gov/news-events/news-releases/janssen-investigational-covid-19-vaccine-interim-analysis-phase-3-clinical-data-released; @url:https://www.janssen.com/emea/sites/www_janssen_com_emea/files/johnson_johnson_announces_single-shot_janssen_covid-19_vaccine_candidate_met_primary_endpoints_in_interim_analysis_of_its_phase_3_ensemble_trial.pdf]. The interim data included 43,783 participants who accrued 468 symptomatic cases of COVID-19. It was reported that the JNJ-78436735 vaccine was 66% effective across all regions studied for the prevention of moderate to severe COVID-19 28 days post-vaccination in those aged 18 years and older. Notably, JNJ-78436735 was 85% effective for the prevention of laboratory-confirmed severe COVID-19 and 100% protection against COVID-19-related hospitalization and death 28 days post-vaccination across all study sites. Efficacy of the vaccine against severe COVID-19 increased over time, and there were no cases of COVID-19 reported in immunized participants after day 49. The trial also determined that the vaccine candidate has a favorable safety profile as determined by an independent Data and Safety Monitoring Board. The vaccine was well tolerated, consistent with previous vaccines produced using the AdVac^®^ platform. Fever occurred in 9% of vaccine recipients, with grade 3 fever occurring in only 0.2% of recipients. Serious adverse events were reportedly higher in the placebo group than the vaccine group, and no anaphylaxis was reported [@url:https://www.janssen.com/emea/sites/www_janssen_com_emea/files/johnson_johnson_announces_single-shot_janssen_covid-19_vaccine_candidate_met_primary_endpoints_in_interim_analysis_of_its_phase_3_ensemble_trial.pdf].
At the time the phase III trial was being conducted, several concerning variants, including B.1.1.7 [@url:https://cov-lineages.org/global_report_B.1.1.7.html] and B.1.351 [@url:https://cov-lineages.org/global_report_B.1.351.html], were spreading across the globe. In particular, B.1.351 was first identified in South Africa, which was one of the JNJ-78436735 vaccine trial sites. Therefore, the J&J investigators also analyzed the efficacy of the JNJ-78436735 vaccine associated with their various trial sites to determine any potential risk of reduced efficacy as a result of the novel variants. It was determined that JNJ-78436735 was 72% effective in the U.S., 66% effective in Latin America, and 57% effective in South Africa 28 days post-vaccination. These findings underpin the importance of monitoring for the emergence of novel SARS-CoV-2 variants and determining their effects on vaccine efficacy.
Looking forward, Janssen are also running a phase III randomized, double-blind, placebo-controlled clinical trial, Ensemble 2, which aims to assess the efficacy, safety, and immunogenicity of a two-dose regimen of JNJ-78436735 administered 57 days apart. This trial will enroll 30,000 participants ≥ 18 years old from Belgium, Colombia, France, Germany, Philippines, South Africa, Spain, U.K., and the U.S. [@url:https://www.jnj.com/johnson-johnson-initiates-second-global-phase-3-clinical-trial-of-its-janssen-covid-19-vaccine-candidate]. This trial will also include participants with and without comorbidities associated with an increased risk of COVID-19.
RNA vaccines are nucleic-acid based modalities that code for viral antigens against which the human body elicits a humoral and cellular immune response. The resulting intracellular viral proteins are displayed on surface MHC proteins, provoking a strong CD8+ T cell response as well as a CD4+ T cell and B cell-associated antibody responses [@doi:10.3389/fimmu.2019.00594]. Given the potential for this technology to be quickly adapted for a new pathogen, it has held significant interest for the treatment of COVID-19. The results of the interim analyses of two mRNA vaccine candidates became available at the end of 2020 and provided strong support for this emerging approach to vaccination. Below we describe in detail the results available as of February 2021 for two such candidates, mRNA-1273 produced by ModernaTX and BNT162b2 produced by Pfizer, Inc. and BioNTech. As of August 2022, the U.S. FDA has issues approvals or emergency use authorizations of versions of these vaccines for adults and for children 6 months and older [@url:https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-moderna-and-pfizer-biontech-covid-19-vaccines-children].
ModernaTX's mRNA-1273 vaccine was the first COVID-19 vaccine to enter a phase I clinical trial in the United States. An initial report described the results of enrolling forty-five participants who were administered intramuscular injections of mRNA-1273 in their deltoid muscle on day 1 and day 29, with the goal of following patients for the next twelve months [@doi:10.1056/NEJMoa2022483]. Healthy males and non-pregnant females aged 18-55 years were recruited for this study and divided into three groups receiving 25, 100, or 250 μg of mRNA-1273. IgG ELISA assays on patient serology samples were used to examine the immunogenicity of the vaccine [@clinicaltrials:NCT04283461]. Binding antibodies were observed at two weeks after the first dose at all concentrations. At the time point one week after the second dose was administered on day 29, the pseudotyped lentivirus reporter single-round-of-infection neutralization assay, which was used to assess neutralizing activity, reached a median level similar to the median observed in convalescent plasma samples. Participants reported mild and moderate systemic adverse events after the day 1 injection, and one severe local event was observed in each of the two highest dose levels. The second injection led to severe systemic adverse events for three of the participants at the highest dose levels, with one participant in the group being evaluated at an urgent care center on the day after the second dose. The reported localized adverse events from the second dose were similar to those from the first.
Several months later, a press release from ModernaTX described the results of the first interim analysis of the vaccine [@url:https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy]. On November 16, 2020, a report was released describing the initial results from phase III testing, corresponding to the first 95 cases of COVID-19 in the 30,000 enrolled participants [@url:https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy], with additional data released to the FDA on December 17, 2020 [@url:https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-december-17-2020-meeting-announcement#event-materials]. These results were subsequently published in a peer-reviewed journal (The New England Journal of Medicine) on December 30, 2020 [@doi:10.1056/NEJMoa2035389]. The first group of 30,420 study participants was randomized to receive the vaccine or a placebo at a ratio of 1:1 [@doi:10.1056/NEJMoa2035389]. Administration occurred at 99 sites within the United States in two sessions, spaced 28 days apart [@url:https://www.fda.gov/media/144434/download; @doi:10.1056/NEJMoa2035389]. Patients reporting COVID-19 symptoms upon follow-up were tested for SARS-CoV-2 using a nasopharyngeal swab that was evaluated with RT-PCR [@url:https://www.fda.gov/media/144434/download]. The initial preliminary analysis reported the results of the cases observed up until a cut-off date of November 11, 2020. Of these first 95 cases reported, 90 occurred in participants receiving the placebo compared to 5 cases in the group receiving the vaccine [@url:https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy]. These results suggested the vaccine is 94.5% effective in preventing COVID-19. Additionally, eleven severe cases of COVID-19 were observed, and all eleven occurred in participants receiving the placebo. The publication reported the results through an extended cut-off date of November 21, 2020, corresponding to 196 cases [@doi:10.1056/NEJMoa2035389]. Of these, 11 occurred in the vaccine group and 185 in the placebo group, corresponding to an efficacy of 94.1%. Once again, all of the severe cases of COVID-19 observed (n=30) occurred in the placebo group, including one death. Thus, as more cases are reported, the efficacy of the vaccine has remained above 90%, and no cases of severe COVID-19 have yet been reported in participants receiving the vaccine.
These findings suggest the possibility that the vaccine might bolster immune defenses even for subjects who do still develop a SARS-CoV-2 infection. The study was designed with an explicit goal of including individuals at high risk for COVID-19, including older adults, people with underlying health conditions, and people of color [@url:https://investors.modernatx.com/news-releases/news-release-details/moderna-has-completed-case-accrual-first-planned-interim]. The phase III trial population was comprised by approximately 25.3% adults over age 65 in the initial report and 24.8% in the publication [@url:https://www.fda.gov/media/144434/download]. Among the cases reported by both interim analyses, 16-17% occurred in older adults [@url:https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy; @doi:10.1056/NEJMoa2035389]. Additionally, approximately 10% of participants identified a Black or African-American background and 20% identified Hispanic or Latino ethnicity [@url:https://www.fda.gov/media/144434/download; @doi:10.1056/NEJMoa2035389]. Among the first 95 cases, 12.6% occurred in participants identifying a Hispanic or Latino background and 4% in participants reporting a Black or African-American background [@url:https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy]; in the publication, they indicated only that 41 of the cases reported in the placebo group and 1 case in the treatment group occurred in "communities of color", corresponding to 21.4% of all cases [@doi:10.1056/NEJMoa2035389]. While the sample size in both analyses is small relative to the study population of over 30,000, these results suggest that the vaccine is likely to be effective in people from a variety of backgrounds.
In-depth safety data was released by ModernaTX as part of their application for an EUA from the FDA and summarized in the associated publication [@doi:10.1056/NEJMoa2035389; @url:https://www.fda.gov/media/144434/download]. Because the detail provided in the report is greater than that provided in the publication, here we emphasize the results observed at the time of the first analysis. Overall, a large percentage of participants reported adverse effects when solicited, and these reports were higher in the vaccine group than in the placebo group (94.5% versus 59.5%, respectively, at the time of the initial analysis) [@url:https://www.fda.gov/media/144434/download]. Some of these events met the criteria for grade 3 (local or systemic) or grade 4 (systemic only) toxicity [@url:https://www.fda.gov/media/144434/download], but most were grade 1 or grade 2 and lasted 2-3 days [@doi:10.1056/NEJMoa2035389]. The most common local adverse reaction was pain at the injection site, reported by 83.7% of participants receiving the first dose of the vaccine and 88.4% upon receiving the second dose, compared to 19.8% and 17.0%, respectively, of patients in the placebo condition [@url:https://www.fda.gov/media/144434/download]. Fewer than 5% of vaccine recipients reported grade 3 pain at either administration. Other frequent local reactions included erythema, swelling, and lymphadenopathy [@url:https://www.fda.gov/media/144434/download]. For systemic adverse reactions, fatigue was the most common [@url:https://www.fda.gov/media/144434/download]. Among participants receiving either dose of the vaccine, 68.5% reported fatigue compared to 36.1% participants receiving the placebo [@url:https://www.fda.gov/media/144434/download]. The level of fatigue experienced was usually fairly mild, with only 9.6% and 1.3% of participants in the vaccine and placebo conditions, respectively, reporting grade 3 fatigue [@url:https://www.fda.gov/media/144434/download], which corresponds to significant interference with daily activity [@url:https://www.fda.gov/media/73679/download]. Based on the results of the report, an EUA was issued on December 18, 2020 to allow distribution of this vaccine in the United States [@url:https://www.cdc.gov/mmwr/volumes/69/wr/mm695152e1.htm], and it was shortly followed by an Interim Order authorizing distribution of the vaccine in Canada [@url:https://investors.modernatx.com/news-releases/news-release-details/health-canada-authorizes-moderna-covid-19-vaccine-canada] and a conditional marketing authorization by the European Medicines Agency to facilitate distribution in the European Union [@url:https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu].
ModernaTX was, in fact, the second company to release news of a successful interim analysis of an mRNA vaccine and receive an EUA. The first report came from Pfizer and BioNTech's mRNA vaccine BNT162b2 on November 9, 2020 [@url:https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against], and a preliminary report was published in the New England Journal of Medicine one month later [@doi:10.1056/NEJMoa2034577]. This vaccine candidate should not be confused with a similar candidate from Pfizer/BioNTech, BNT162b1, that delivered only the RBD of the spike protein [@doi:10.1038/s41586-020-2639-4; @doi:10.1038/s41586-020-2814-7], which was not advanced to a phase III trial because of the improved reactogenicity/immunogenicity profile of BNT162b2 [@doi:10.1056/NEJMoa2027906].
During the phase III trial of BNT162b2, 43,538 participants were enrolled 1:1 in the placebo and the vaccine candidate and received two 30-μg doses 21 days apart [@doi:10.1056/NEJMoa2034577]. Of these enrolled participants, 21,720 received BNT162b2 and 21,728 received a placebo [@doi:10.1056/NEJMoa2034577]. Recruitment occurred at 135 sites across six countries: Argentina, Brazil, Germany, South Africa, Turkey, and the United States. An initial press release described the first 94 cases, which were consistent with 90% efficacy of the vaccine at 7 days following the second dose [@url:https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against]. The release of the full trial information covered a longer period and analyzed the first 170 cases occurring at least 7 days after the second dose, 8 of which occurred in patients who had received BNT162b2. The press release characterized the study population as diverse, reporting that 42% of the participants worldwide came from non-white backgrounds, including 10% Black and 26% Hispanic or Latino [@url:https://www.pfizer.com/science/coronavirus/vaccine]. Within the United States, 10% and 13% of participants, respectively, identified themselves as having Black or Hispanic/Latino backgrounds [@url:https://www.pfizer.com/science/coronavirus/vaccine]. Additionally, 41% of participants worldwide were 56 years of age or older [@url:https://www.pfizer.com/science/coronavirus/vaccine], and they reported that the efficacy of the vaccine in adults over 65 was 94% [@url:https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine]. The primary efficacy analysis of the phase III study was concluded on November 18, 2020 [@url:https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine], and the final results indicted 94.6% efficacy of the vaccine [@doi:10.1056/NEJMoa2034577].
The safety profile of the vaccine was also assessed [@doi:10.1056/NEJMoa2034577]. A subset of patients were followed for reactogenicity using electronic diaries, with the data collected from these 8,183 participants comprising the solicited safety events analyzed. Much like those who received the ModernaTX vaccine candidate, a large proportion of participants reported experiencing site injection pain within 7 days of vaccination. While percentages are broken down by age group in the publication, these proportions correspond to approximately 78% and 73% of all participants after the first and second doses, respectively, overall. Only a small percentage of these events (less than 1%) were rated as serious, with the rest being mild or moderate, and none reached grade 4. Some participants also reported redness or swelling, and the publication indicates that in most cases, such events resolved within 1 to 2 days. Participants also experienced systemic effects, including fever (in most cases lower than 38.9°C and more common after dose 2), fatigue (25-50% of participants depending on age group and dose), headache (25-50% of participants depending on age group and dose), chills, and muscle or joint pain; more rarely, patients could experience gastrointestinal effects such as vomiting or diarrhea. As with the local events, these events were almost always grade 1 or 2. While some events were reported by the placebo groups, these events were much rarer than in the treatment group even though compliance was similar. Based on the efficacy and safety information released, the vaccine was approved in early December by the United Kingdom's Medicines and Healthcare Products Regulatory Agency with administration outside of a clinical trial beginning on December 8, 2020 [@doi:10.1136/bmj.m4714; @url:https://www.bbc.com/news/uk-55227325]. As of December 11, 2020, the United States FDA approved this vaccine under an emergency use authorization [@url:https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19], and in August 2021, it received full approval for ages 16 and older [@url:https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine].
Prior to studies examining the effectiveness of vaccines in real-world settings (summarized in [@individual-vaccines-novel], several studies reported reduced efficacy of the mRNA vaccines based on the measurement of antibody titers. Plasma from individuals double-dosed with Pfizer/BioNTech's BNT162b2 vaccine had up to a 16-fold reduction in neutralizing capacity against the Omicron variant [@doi:10.1101/2021.12.14.21267772] and a reduced efficacy (70%) [@doi:10.1056/NEJMc2119270]. Estimates for the mRNA vaccines range from a 2-fold to over a 20-fold drop in neutralisation titers [@doi:10.1101/2021.12.13.21267748], hence the push for third and fourth doses of mRNA vaccines in many Western countries. A third mRNA vaccine dose does increase antibody titers, but these levels also wane with time [@doi:10.15585/mmwr.mm7107e2]. Notably, immunocompromised individuals such as cancer patients seem to elicit a sufficient protective immune response against the Omicron variant when they have been boosted with a third dose of either mRNA vaccine, albeit a blunted response [@doi:10.1016/j.ccell.2021.12.014]. While antibody titers do correlate with protection [@doi:10.1126/science.abm3425; @doi:10.1016/j.vaccine.2021.12.006; @doi:10.1016/j.vaccine.2021.05.063; @doi:10.1101/2021.05.21.21257572; @doi:10.1038/s41423-020-00588-2], they are not the only mechanisms of immune protection. For example, T cell and non-neutralizing antibody responses may be unaffected or less affected by the new VOC, and they warrant further investigation.
In North America, the majority of vaccines distributed until March 2021 have been produced by Pfizer-BioNTech and Moderna. In Canada, the vaccine approval process is conducted by Health Canada, which uses a fast-tracked process whereby vaccine producers can submit data as it becomes available to allow for rapid review. An approval may be granted following reviews of the available phase III clinical data. This is followed by a period of pharmacovigilance in the population using their post-market surveillance system, which will monitor the long-term safety and efficacy of any vaccines [@41tJkg7h; @safety-after-authorization]. Health Canada has authorized the use of the Pfizer (December 9th, 2020), Moderna (December 23rd, 2020), Oxford-AstraZeneca (February 26th, 2021), and the Janssen (March 5th, 2021) vaccines, and the Novavax Inc vaccine is also under consideration [@ZHZjD4YC]. While Canada initially projected that by the end of September 2021 a vaccine would be available for all Canadian adults, they now predict that it may be possible earlier as more vaccines have been approved and become available [@url:https://www.cbc.ca/news/politics/trudeau-possible-vaccination-campaign-ends-sooner-1.5934994].
In the U.S., vaccines are required to have demonstrated safety and efficacy in phase III trials before manufacturers apply for an emergency use authorization (EUA) from the FDA. If an EUA is granted, an additional evaluation of the safety and efficacy of the vaccines is conducted by the CDC’s Advisory Committee on Immunization Practices (ACIP) who also provide guidance on vaccine prioritization. On December 1st, 2020, ACIP provided an interim phase 1a recommendation that healthcare workers and long-term care facility residents should be the first to be offered any vaccine approved [@doi:10.15585/mmwr.mm6949e1]. This was shortly followed by an EUA on December 11th, 2020 for the use of the Pfizer-BioNTech COVID vaccine [@doi:10.15585/mmwr.mm6950e2], which was distributed and administered to the first healthcare workers on December 14th, 2020 [@{url:https://abcnews.go.com/US/us-administer-1st-doses-pfizer-coronavirus-vaccine/story?id=74703018}]. Shortly thereafter, an EUA for the Moderna vaccine was issued on December 18th, 2020 [@doi:10.15585/mmwr.mm695152e1]. On December 20th, 2020, ACIP updated their initial recommendations to suggest that vaccinations should be offered to people aged 75 years old and older and to non-healthcare frontline workers in phase 1b [@doi:10.15585/mmwr.mm695152e2]. On the same date, it was recommended that phase 1c should include people aged 65-74 years old, individuals between the ages of 16-74 years old at high-risk due to health conditions, and essential workers ineligible in phase 1b [@doi:10.15585/mmwr.mm695152e2]. On the following day, December 21st, 2020, the first Moderna vaccines used outside of clinical trials were administered to American healthcare workers, which was the same day that President-elect Biden and Dr. Biden received their first doses of the Pfizer-BioNTech vaccine live on television to instill confidence in the approval and vaccination process [@url:https://www.cnn.com/2020/12/21/health/us-coronavirus-monday/index.html].
On February 27th, 2020, the FDA issued an EUA for the Janssen COVID-19 Vaccine [@url:https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine]. This was followed by an update on recommendations by ACIP for the use of the Janssen COVID-19 vaccine for those over 18 years old [@doi:10.15585/mmwr.mm7009e4]. The Janssen vaccine was first distributed to healthcare facilities on March 1st, 2021. On March 12, 2021, the WHO added the Janssen vaccine to the list of safe and effective emergency tools for COVID-19 [@url:https://www.who.int/news/item/12-03-2021-who-adds-janssen-vaccine-to-list-of-safe-and-effective-emergency-tools-against-covid-19]. While the CDC’s ACIP can provide recommendations, it is up to the public health authorities of each state, territory, and tribe to interpret the guidance and determine who will be vaccinated first [@url:https://www.hhs.gov/coronavirus/covid-19-vaccines/distribution/index.html]. Prior to distribution of the Janssen vaccine, over 103 million doses of the Moderna and Pfizer-BioNTech vaccines were delivered across the U.S., with almost 79 million doses administered. Of the total population, 15.6% have received at least one dose and 7.9% have received a second dose of either the Moderna (~38.3 million) or the Pfizer-BioNTech (~40.2 million) vaccines by February 28th, 2021 [@{url:https://covid.cdc.gov/covid-data-tracker/#vaccinations}]. President Biden’s administration has predicted that by the end of May 2021 there may be enough vaccine supply available for all adults in the U.S. [@{url:https://www.cnn.com/2021/03/02/politics/biden-merck-johnson--johnson-vaccine/index.html}; @url:https://www.bbc.com/news/world-us-canada-55721437]. However, vaccine production, approval, and distribution was not straightforward in the U.S., as information was initially sparse and the rollout of vaccines was complicated by poor planning and leadership due to political activities prior to the change of administration in January 2021 [@{url:https://ssrn.com/abstract=3770368}]. These political complications highlight the importance of the transparent vaccine approval process conducted by the FDA [@doi:10.1001/jama.2021.1961].
Outside the U.S., the Moderna and Pfizer-BioNTech vaccines have been administered in 29 and 69 other countries, respectively, mainly in Europe and North America [@url:https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html]. The Janssen vaccine has so far only been administered in South Africa and the U.S. [@url:https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html; @url:https://www.biopharma-reporter.com/Article/2021/02/18/South-Africa-starts-administering-Janssen-COVID-19-vaccine-to-health-workers], but it has also been approved in Bahrain, the European Union (E.U.), Iceland, Liechtenstein, and Norway [@url:https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html]. On March 11th, 2021, Johnson & Johnson received approval from the European Medicines Agency (EMA) for conditional marketing authorization of their vaccine [@ema-janssen]. Notably, on March 2nd, 2021, rivals Johnson & Johnson and Merck announced that they entered an agreement to increase production of the Janssen vaccine to meet global demand [@url:https://www.washingtonpost.com/health/2021/03/02/merck-johnson-and-johnson-covid-vaccine-partnership].
The U.K. was the first country to approve use of the Pfizer-BioNTech vaccine on December 2nd, 2020 [@doi:10.1038/d41586-020-03441-8], and it was later approved by EMA on December 21st, 2020 [@ema-first]. The U.K. was also the first to administer the Pfizer-BioNTech vaccine, making it the first COVID-19 vaccine supported by phase III data to be administered outside of clinical trials on December 8th, 2020. The Oxford-AstraZeneca vaccine, was approved by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the U.K. and by EMA in the E.U. on December 30th (2020) [@url:https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca] and January 29th (2021) [@ema-astrazeneca], respectively. The Oxford-AstraZeneca vaccine was first administered in the UK on January 4th, 2021 [@url:https://www.bbc.com/news/uk-55525542], and it is now being used in 53 countries in total, including Brazil, India, Pakistan, Mexico, and spanning most of Europe [@url:https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html]. The Moderna vaccine was authorized for use in the E.U. by EMA on January 6th, 2021 [@ema-spikevax] and in the U.K. by MHRA on January 8th, 2021 [@url:https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna]. As of March 5th, 2021, 22 million people in the U.K. had received at least one vaccine dose [@url:https://ourworldindata.org/covid-vaccinations].
While the Pfizer-BioNTech vaccine was the first to be distributed following phase III clinical trials, the first COVID-19 vaccine to be widely administered to people prior to the completion of phase III clinical trials was Sputnik V. Sputnik V was administered to as many as 1.5 million Russians by early January [@url:https://www.brusselstimes.com/news-contents/world/149039/1-5-million-people-have-received-sputnik-v-vaccine-russia-says-russian-direct-investment-fund-mikhail-murashko] due to the establishment of mass vaccination clinics in December 2020, prior to which only approximately 100,000 Russians had already been vaccinated [@url:https://www.bloomberg.com/news/articles/2020-12-02/within-hours-of-u-k-putin-orders-start-of-mass-covid-19-shots;@{url:https://www.forbes.com/sites/jamesrodgerseurope/2020/12/05/facing-record-covid-19-case-rise-russia-rolls-out-sputnik-v-vaccine}]. Doses of Sputnik V have also been distributed to other parts of Europe [@url:https://www.euronews.com/2021/02/12/hungary-to-begin-using-russia-s-sputnik-v-vaccine-today; @url:https://www.euronews.com/2021/02/24/san-marino-buys-russia-s-sputnik-v-after-eu-vaccine-delivery-delays; @url:https://www.themoscowtimes.com/2020/12/29/belarus-starts-coronavirus-vaccination-with-sputnik-v-a72512]. Hungary was the first E.U. member country to approve and distribute Sputnik V outside of Russia [@url:https://www.cnbc.com/2021/03/02/russias-sputnik-vaccine-is-luring-eastern-europe-worrying-the-eu.html], despite the EMA stating that they had neither approved nor received a request for approval of Sputnik V [@ema-sputnik-clarification]. Hungary is also in talks with China to procure the Sinopharm vaccines, which have been approved by Hungarian health authorities but also have not received approval by EMA in the E.U. [@url:https://www.cnbc.com/2021/03/02/russias-sputnik-vaccine-is-luring-eastern-europe-worrying-the-eu.html]. In Latin America, production facilities in both Brazil and Argentina will allow for increased production capacity of Sputnik V and doses have been distributed to Mexico, Argentina, Bolivia, Nicaragua, Paraguay, and Venezuela [@https://fortune.com/2021/02/08/international-sputnik-russia-demand]. Guinea was the first African nation to administer Sputnik V in December 2020, and the Central African Republic, Zimbabwe, and the Ivory Coast have all registered their interest in purchasing doses of the vaccine [@https://fortune.com/2021/02/08/international-sputnik-russia-demand]. In the Middle East, Iran has received its first doses of Sputnik V and the United Arab Emirates is conducting phase III trials [@https://fortune.com/2021/02/08/international-sputnik-russia-demand]. In Asia, while China’s vaccine candidates are favored, the Philippines, Nepal, and Uzbekistan have sought Sputnik V doses [@url:https://sputnikvaccine.com/newsroom/pressreleases/rdif-announces-delivery-of-the-first-batch-of-sputnik-v-vaccine-to-venezuela-for-clinical-trials]. In total, the RDIF claims to have received orders totalling 1.2 billion doses by over 50 countries worldwide [@url:https://sputnikvaccine.com/newsroom/pressreleases/rdif-announces-delivery-of-the-first-batch-of-sputnik-v-vaccine-to-venezuela-for-clinical-trials] and at least 18 countries are currently administering Sputnik V around the globe [@url:https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html]. Sputnik V has been an attractive vaccine for many countries due to its relatively low price, high efficacy, and its favorable storage conditions. For some countries, Russia and China have also been more palatable politically than vaccine suppliers in the West [@https://fortune.com/2021/02/08/international-sputnik-russia-demand; @url:https://www.politico.com/news/2021/02/25/global-vaccine-public-relations-war-471665]. For others, the delays in the distribution of the other, more-favored candidates has been a motivating factor for pursuing the Sputnik V and Chinese alternatives [@url:https://www.politico.com/news/2021/02/25/global-vaccine-public-relations-war-471665; @url:https://www.euronews.com/2021/02/24/san-marino-buys-russia-s-sputnik-v-after-eu-vaccine-delivery-delays]. Additionally, Germany has stated that if Sputnik V were approved by EMA, it would be considered by the E.U. [@url:https://www.france24.com/en/live-news/20210203-germany-moves-to-bring-russian-vaccine-into-eu-orbit]. Russia is developing other vaccine candidates and has approved a third vaccine, CoviVac, which is an inactivated vaccine produced by the Chumakov Centre in Moscow, despite the fact the clinical trials have yet to begin [@url:https://www.reuters.com/article/us-health-coronavirus-russia-vaccine-idUSKBN2AK07H].