Special Rewind: COVID-19 Vaccine Edition. December 21, 2020

Section 1: Pfizer/BioNTech Vaccine First to Receive Emergency Use Authorization to Prevent COVID-19

On December 11, 2020, the U.S. Food and Drug Administration (FDA) approved for emergency use the first vaccine to prevent coronavirus disease 2019 (COVID-19).1 This vaccine includes BNT162b2, a lipid nanoparticle-formulated, nucleoside-modified RNA and encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein.2 The safety and efficacy of this vaccine, funded by Pfizer and BioNTech, have been studied, with a Phase 2/3 study of 43,548 participants suggesting that two 30μg doses of BNT162b2 three weeks apart is 95% effective in preventing COVID-19 (95% credible interval 90.3 to 97.6). This finding was similar across subgroups of age, race, sex, ethnicity, BMI and coexisting medical conditions (90-100%).3 Further, between vaccine and placebo groups, cumulative incidence of COVID-19 diverges by 12 days after the first dose, which is 7 days after the estimated median viral incubation period. A total of 10 severe COVID-19 cases arose after the first vaccine dose, with only one of these occurring in the BNT162b2 group. Though more patients that received the vaccine dose reported related adverse events (21% versus 5%), this was primarily due to the inclusion of transient reactogenicity events such as fever and chills that resolved within 2 days post vaccination. Serious adverse events were rare and similar across both vaccine and placebo groups (<0.0001%). As such, the reported safety profile was limited to fatigue, headache, and transient, mild-to-moderate pain at injection site. Ultimately, this vaccine demonstrated itself to be 95% effective in preventing COVID-19. The early batches of the Pfizer/BioNTech vaccine will only be enough for approximately 3.2 million people, such that the Centers for Disease Control and Prevention (CDC) has had to focus recommendations on who should receive these early vaccines. Frontline healthcare workers and residents of long-term care facilities will be among those receiving vaccines early in the process.4 States have been tasked with prioritizing the needs of its residents, with variation across the country based on where it stands with COVID-19 cases. Further, specific facilities are required for the cool storage of the vaccine, which places smaller hospitals and under-resourced areas at a disadvantage. However, the Pfizer/BioNTech vaccine is a landmark opportunity to control the virus with proven efficacy and safety in the coming months as other vaccines seek approval.


Section 2: Moderna Vaccine Second to Receive Emergency Use Authorization

The FDA Advisory Committee met on December 17, 2020, ultimately recommending the Moderna vaccine’s approval for emergency use in the prevention of COVID-19. After hospitals across the U.S. began to receive batches of the Pfizer/BioNTech vaccine, Moderna has become the second to receive FDA approval. This candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein,1 which is similar in mechanism to the Pfizer/BioNTech vaccine previously approved. This vaccine, specifically, uses the mRNA platform with the stabilized SARS-CoV-2 spike immunogen (S-2P), which was developed by NIAID scientists.2 This Phase 1, dose-escalation, open-label trial was published on July 14, 2020.3 The study recruited 45 healthy adults between the ages of 18 and 55 years to receive two intramuscular injections 28 days apart with an equal number of participants in the 25μg, 100μg, and 250μg dose groups. Antibody responses were assessed after the first vaccination and were shown to be dose-dependent with day 29 enzyme-linked immunosorbent assay anti-S2P antibody geometric mean titer (GMT) of 40,227(25μg), 109,209 (100μg), and 213,526 (250μg). Day 57 GMT, following the second vaccination, titers increased further to 299,751(25μg), 782,719(100μg), and 1,192,154(250μg). Serum-neutralizing activity was detected in all participants via two methods. Fatigue, myalgia, chills, headache, and pain at injection site were reported in ≥50% of participants. Three participants (21%) in the 250μg dose group reported at least one severe adverse event. Overall, no trial-limiting safety concerns arose, such that development has been able to continue. On November 30, 2020, Moderna reported final results of their efficacy trial of 30,000 participants, demonstrating that only 11 participants who received two doses of the vaccine developed COVID-19 symptoms, compared to 185 participants in the placebo group, boasting 94% effectiveness. More importantly, no serious COVID-19 cases arose among any participants who received two doses of Moderna’s vaccine.4,5 The U.S. has already purchased 200 million shots of the Moderna vaccine, which will assist in ensuring that enough Americans can be vaccinated by mid-2021.6 While vaccines often take decades to develop and distribute, the speed with which COVID-19 vaccines have been developed is not a cause for concern – it is attributable to advances in computational biology, protein engineering, gene synthesis, and structure-based antigen design.7 Scientific advancement has allowed for rapid development and emergency distribution.


Section 3: Oxford/AstraZeneca Vaccine Shows Promise for Phase 3 Outcomes

With many COVID-19 vaccine being studied and approved for emergency use, one important candidate is the chimpanzee adenovirus-vector (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein.1 The University of Oxford developers of this vaccine have a partnership with AstraZeneca. This Phase 1/2 single-blinded, randomized controlled trial at five sites in the UK compared safety, immunogenicity, and reactogenicity of ChAdOx1 nCoV-19 compared to a meningococcal conjugate vaccine (MenACWY).2 Participants included were between the ages of 18 and 55 years with no history of laboratory-confirmed SARS-CoV-2 or known symptoms were assigned 1:1 to receive either ChAdOx1 nCoV-19 at 5 x 1010 viral particles or a single intramuscular injection of MenACWY. Two of the five sites amended a protocol, thereby permitting the use of prophylactic paracetamol prior to vaccination. Humoral responses were assessed at baseline and follow-up after a single-dose vaccination with a standardized total IgG ELISA against trimeric SARS-CoV-2 spike protein, multiplexed immunoassay, three live SARS-CoV-2 neutralization assays, and a pseudovirus neutralization assay. Cellular responses were assessed at the same timepoints with an ex-vivo interferon-γ enzyme-linked immunospot assay. A total of 1,077 participants were assigned to receive either ChAdOx1 nCoV-19 (n = 153) or MenACWY (n = 534). Safety was assessed over the course of 28 days post-vaccination. Systemic and local reactions were found to be more common in the ChAdOx1 nCoV-19 group compared to the MenACWY group, but were similar to the Pfizer/BioNTech in being primarily composed of transient reactogenicity reactions such as chills, muscle ache, headache, malaise, fever, and pain (p<0.05), that were reduced with prophylactic paracetamol. No serious adverse events were reported with the ChAdOx1 nCoV-19 vaccine. Spike-specific T-cell responses peaked at 14 days (median 856 spot-forming cells/1,000,000 peripheral blood mononuclear cells, IQR 493 to 1802, n = 43). Neutralizing antibody responses were detected in 91% of 35 participants after first dose when measured in MNA80 and 100% of these participants when measured in PRNT50. Anti-spike IgG responses rose at 28 days (median 157 ELISA units [EU], 96 to 317, n = 127) and were further boosted after second dose (639 EU, 360 to 792, n = 10). Overall, ChAdOx1 nCoV-19 was shown to be a safe vaccine that increased antibody responses with potential for positive Phase 3 outcomes.


Section 4: Johnson & Johnson One of Top 5 COVID-19 Vaccine Finalists

The Johnson & Johnson (J&J) Pharmaceutical Research and Development group has focused its COVID-19 vaccine efforts on a single-dose replication-defective human adenovirus 26 vector (Ad26.COV2.S).1,2,3 This vector deliver recombinant SARS-CoV-2 S protein genes to human cells. While no vaccines of this type are commercially available to prevent human disease, the one licensed vaccine is for the prevention of animal rabies. Development has moved into a Phase 2-2a trial supported by $456 million in grants, aiming to recruit up to 30,000 participants. This phase entails the evaluation of the effectiveness and safety of the vaccine, which follows studies on healthy individuals with various dose ranges in Phase 1. Phase 2a, specifically, aims to identify dosing requirements as well as optimal frequency of dosing. Should the study move to Phase 2b, they will directly assess its efficacy in preventing COVID-19.4 J&J, along with Janssen Vaccines & Prevention, published a preprint of clinical trial results assessing the efficacy of AD26.COV2.S in preventing moderate-to-severe COVID-19 in adults.5 A multicenter Phase 1/2a randomized, double-blinded, placebo-controlled study assessed safety, immunogenicity, and reactogenicity of Ad26.COV2.S at a dose level of 5 x 1010 or 1 x 1011 viral particles (vp) per vaccination, in either single dose or two doses 56 days apart in healthy individuals (18-55 years n = 402; >65 years n = 394). Fatigue, headache, myalgia, and pain at injection site were the most frequent adverse events. After a single dose, seroconversion rate in wtVNA (50% inhibitory concentration – IC50) at day 29 among adults 18-55 years reached 92% for both dose levels. Overall, this study found that a single 5 x 1010 vp dose of Ad26.COV2.S may be protective against COVID-19.


Section 5: Other Promising Vaccine Candidates and Considerations

Messenger RNA (mRNA) vaccines have offered a novel methodology in the context of COVID-19, including the Pfizer/BioNTech1 and Moderna2 vaccines. Rather than placing a weak or inactivated germ into the human body, mRNA vaccines  utilize host cells to make a protein that triggers an immune response and, in turn, produces antibodies to prevent future infection.3,4 Despite the common misconception, mRNA vaccines never enter cell nuclei and are therefore unable to alter host DNA in any capacity. These mRNA vaccines have been under development for decades.5 University of Oxford/AstraZeneca6 and Johnson & Johnson/Janssen Pharmaceuticals7 have focused on adenovirus vector approaches to the vaccine, which also show promise in preventing COVID-19. Another candidate vaccine uses recombinant vesicular stomatitis virus vector (V591),8 which is being developed by Merck Sharpe and Dohme, and the International AIDS Vaccine Initiative.9,10 This approach is similar to Erverbo, the recombinant stomatitis virus-vectored Ebola Zaire live vaccine, also developed by Merck Sharp and Dohme. Beginning on August 27, 2020, this Phase 1/2 randomized, double-blind, placebo-controlled, dose-ranging trial sought to evaluate safety, tolerability, and immunogenicity of single- and double-dose V591 administered via intramuscular injection. Merck Sharp and Dohme also began a Phase 1 trial for dose-ranging of V590 on October 29, 2020, which includes a single dose via intramuscular injection (5.00 x 105pfu/mL, 2.40 x 106pfu/mL, 1.15 x 107pfu/mL, 5.55 x 107pfu/mL).11 Despite the promising vaccine candidates being authorized and developed, there are still several barriers that must be confronted to ensure broad public safety. Not only is resource allocation essential, but we must be cognizant of the health disparities that exist and ensure that we do not further perpetuate them. Prioritizing vaccine allocation based on race/ethnicity is an ethically and legally contentious topic,11 but people of color are disproportionately represented among COVID-19 cases and deaths.12,13 People of color are also underrepresented among clinical trials. After frontline healthcare workers and residents of long-term living facilities are vaccinated,14 the next group will need to be carefully prioritized. Further, vaccines are likely to face scrutiny by a subgroup of people. A Pew Research Center survey from September 2020 found that nearly 49% of respondents ‘definitely or probably would not’ get vaccinated,15 though this was earlier in vaccine development. With multiple vaccines reaching the market by Summer 2021, information will continue to be collected to ensure long-term tolerability, absence of adverse events, and control of any allergic reactions. With 16,897,911 total cases and 309,880 deaths due to COVID-19 in the U.S. as of December 18, 2020,16 it is critical that states and the general public view vaccination from an apolitical, scientific perspective. This will need to be supplemented by patient education and culturally-competent practice that understands the mistrust felt toward healthcare professionals and pharmaceutical companies, particularly among people of color.17, 18

Image: PD

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