Current COVID-19 Vaccine Trials
Overview
The race for a SARS-CoV-2 vaccine draws similar parallels to the 1950s race for the moon. Although there is a question about “who’s first?”, the real analogy comes from the final achievement. For humanity in 2020, it is defeating COVID-19. And in this quest to return to normal life, there are several companies developing vaccines that make differentiating the candidates and understanding the science behind them can be seemingly impossible. This article will discuss the basics of each vaccine in Phase 3 testing for major companies in the race for a SARS-CoV-2 vaccine. Additionally, there will be brief mentions of companies in earlier phases of vaccine testing.
For a deeper understanding on vaccines, visit Applied OC’s article on Vaccines: the Basics.
Novavax
Novavax has developed a vaccine, called NVX-CoV2373, that can be categorized as recombinant nanoparticle technology. In simpler words, the vaccine contains an antigen similar to the glycoproteins (spikes) found on the surface of SARS-CoV-2, the virus that causes COVID-19. The antigen was specifically designed to interact with human receptors similar to SARS-CoV-2 in order to elicit an immune response.
In May of 2020, Novavax began round 1 of Phase 1/2 clinical trials. In August of 2020, they posted results, indicating that NVX-CoV2373 adjuvanted, or boosted, with Matrix-M (a serum that improves immunological responses) was “generally well-tolerated and elicited robust antibody responses.” Round 2 of Phase 1/2 testing began near the end of August 2020 where the company expanded the age range of the tested population to include 60-84 year adults.
Before Phase 1/2 testing ended, the company began Phase 3 testing of the vaccine near the end of September of 2020. The 3rd round is intentional to testing on a larger scale, near 10,000 individuals, in order to be more representative of the human population.
AstraZeneca (AZ)
The AZD1222 (ChAdOx1 nCoV-19) vaccine from AstraZeneca (AZ) is a non-replicating viral vector vaccine. Essentially, the company uses a weakened common cold virus as a carrier of genetic information of SARS-CoV-2. This mechanism utilizes the virus’s capability of inserting its own genetic code into the infected individual while only risking the illness of the common cold rather than potentially harmful symptoms of COVID-19. From there, human cells can recognize foreign DNA in order to initiate and promote an immune response.
AZ ran a trial on a single dose of AZD1222 on rhesus macaques (primates). Protection against lower respiratory tract infections was observed. Following this pre-human trial, AstraZeneca ran a single-blind, randomized Phase 1/2 trial from April to May where participants either received AZD1222 or MenACWY, a meningococcal vaccine, which acted as a control. The company concluded that the single dose of AZD1222 was safe and tolerated despite increased systemic and local reactions compared to the control, MenACWY. Participants who received AZD1222 reported higher instances of fatigue and headaches that were categorized as only mild or moderate side effects. Overall, neutralizing antibodies were observed after a single-dose and, in fact, increased after a second-dose booster was administered.
In August of 2020, AZ & the University of Oxford entered into the Phase 3 of testing, the largest round of testing completed by the company so far. The trial spans multiple sites in the US and the UK. However, only a week after testing began, the trial was stalled due to an unknown severe adverse reaction occuring in the United Kingdom. It was later released that a female participant developed transverse myelitis, an inflammation syndrome in the spinal cord. After a week of review, AZ resumed the trial with permission from a Medical Regulatory institution.
Johnson & Johnson (Janssen Pharmaceutical Company)
Similar to AstraZeneca, Johnson & Johnson’s (J&J) SARS-CoV-2 vaccine, JNJ-78436735, is categorized as a non-replicating viral vector. In collaboration with Beth Israel Deaconess Medical Center and Harvard Medical School, the vaccine has been designed with the use of J&J’s AdVac technology and noted to be the leading candidate for a single-dose vaccine. In comparison to AstraZeneca, this vaccine uses a different variation of the common cold that introduces similar SARS-CoV-2 genetic material.
In July of 2020, J&J announced the results of their non-human primate trials with conclusions of robust immune response that included neutralizing antibodies for SARS-CoV-2. Phase 1/2a of human trials began mid-July, which tested the tolerance and reactions to the vaccine while also testing the immune response of over 1,000 participants. The midpoint conclusions of that test were that, at 29 days post vaccination, 98% of the participants were positive for neutralizing antibodies after a single-dose. As for adverse effects, symptoms were mild to moderate and, typically, appeared the day of vaccination, but subsided several hours later. Participants are still planning to receive a second dose before the trial is complete.
J&J announced the start of Phase 3 human trials, called ENSEMBLE, at the end of September 2020 where they will be testing the single-dose used in Phase 1/2a on about 60,000 volunteers across 3 continents. However, as of mid-October, J&J put a study pause on the testing due to an unexplained illness in one of their participants. Phase 3 has yet to resume, yet there is a hope for resolution soon. J&J also plans to conduct another trial that includes a two-dose regimen later this year depending on the final results of Phase 1/2a.
Moderna
Moderna is one of only a few companies that have designed an mRNA-based vaccine, mRNA-1273. After isolating SARS-CoV-2 and sequencing its genetic code, the company translated the genetic code of the spike protein into mRNA (messenger genetic code that relays blueprints to protein synthesizing machines). As a vaccine, the mRNA is housed in a lipid nanoparticle, which is injected into immune cells and instructs them to begin making the spike protein as if it was infected by SARS-CoV-2. Other immune cells can recognize the proteins and create a defense against SARS-CoV-2 if the individual was ever infected.
Phase 1 testing began in February 2020 with candidates ranging from 18 to 71+ years of age. The trial is officially concluded with final results posted as of September 2020. The purpose of the trial was to determine which dose was best after one and two-doses. The researchers noted that the adverse reactions ranged from mild to moderate in severity, typically fatigue, headache, muscle aches, and pain at the injection site. The study concluded that the higher dose induced larger amounts of neutralizing-antibody titers.
Phase 2 testing began in late May 2020 where researchers are specifically testing two different doses in comparison to a placebo. Phase 3 trials began in late July where an expected 30,000 candidates will be randomly injected with either a 100mg vaccine or a placebo due to the results of Phase 1 testing. The researchers are specifically testing for prevention of severe COVID-19 symptoms and prevention of SARS-CoV-2 infection.
Sinovac
Sinovac designed CoronaVac, a vaccine that utilizes an inactivated form of SARS-CoV-2. This biopharmaceutical company cultured the COVID-19 virus and removed its disease-causing components in order to safely introduce the viral particles in an individual without risk of transmission to others. This type of vaccination is utilized for common vaccines: Hepatitis A, Rabies, and Influenza.
In June of 2020, Sinovac posted their results of the first round of Phase 1/2 testing, where they tested a single dose of CoronaVac in participants aged 18 to 59 years old. The results showed a strong positive outcome of seroconversion (production of neutralizing antibodies) with adverse reactions falling into a mild category. Phase 1/2 expanded to a second round, where participants 60 years and older were tested in a two-dose procedure of CoronaVac in 3 different doses: low, medium, and high. The results of seroconversion were comparable to the first round of testing, and slightly higher for the medium dosage. From these results, Sinovac was approved for Phase 3 testing, where the company plans to utilize a two immunization technique with medium dosage.
Phase 3 testing with Butantan Institute in Brazil began in July of 2020 with the recruitment of almost 9,000 healthcare professionals specifically working in COVID-19 facilities. Results are still pending for Phase 3 testing. Additionally, in September of 2020, Sinovac began working with the Health Institute of Turkey in a clinical trial to test the efficacy of CoronaVac by testing an estimated 13,000 participants. Volunteers will be separated into cohorts based on COVID-19 risk and will randomly receive either CoronaVac or a placebo.
Pfizer & BioNTech
Pfizer and BioNTech have developed a vaccine, BNT162, that is mRNA based. Similar to Moderna, the mRNA is bound inside lipid nanoparticles in order to protect and help the material enter the body’s cells before instructing it to begin making viral proteins. The immune system will then recognize the foreign particles and begin a response to protect against SARS-CoV-2 without introducing live viruses. Unlike Moderna, Pfizer and BioNTech has expanded their testing and vaccine to include 3 different mRNAs testing them individually.
Pfizer and BioNTech designed testing as one large clinical trial with 3 rounds, Phase 1/2/3. Phase 1 testing of BNT162 began in late April where participants were randomly treated with two doses of a placebo or one of two BNT162 candidates: b1 and b2 – where each holds mRNA that instructs the production of different SARS-CoV-2 proteins. Additionally, the companies tested the elevation of dosage.
The results of Phase 1 indicated that BNT162b2 elicited less incidence and severity of symptoms in older adults than BNT162b1, while both candidates elicited similar dose-dependent responses in younger participants. Pfizer and BioNTech chose BNT162b2 as the candidate for evaluation in Stages 2/3 of the clinical trial, where testing expands on cohorts and efficacy of the vaccine at a mid-dose level.
CanSino Biologics
In collaboration with the Beijing Institute of Biotechnology, CanSino Biologics developed a COVID-19 vaccine, Ad5-nCoV, that uses Adenovirus Type 5 as a vector. In other words, the vaccine utilizes a modified common cold virus to transmit SARS-CoV-2 genetic information that limits the severity of symptoms and inhibits the transmission of the virus. This vaccination type is similar to AstraZeneca’s method. However, AZ utilizes a different serotype (subspecies) of the Adenovirus.
CanSino began Phase 1 testing in March of 2020 by screening over 100 participants aged 18 to 60 years old. The study was non-randomized and escalated by dosage of a single injection. Results indicated mild and moderate adverse reactions, some associated with the Adenovirus Type 5. The researchers saw good immune responses in all, yet decided to further experiments with low- and medium-dose vaccinations. Further analysis was inappropriate due to the non-randomized and non-blind characteristics of the study.
A month following, CanSino started Phase 2 testing with over 500 participants. Unlike Phase 1, this clinical trial was randomized, double-blind, and placebo controlled, yet it was still a single injection. Similar to Phase 1, participants experienced mild and moderate symptoms. Overall, the vaccination showed an increase in neutralizing antibodies for SARS-CoV-2. Additionally, researchers saw no considerable difference between the immune responses of those who received the low-dose versus the medium-dose. There is consideration to add a second injection 6 months after the initial vaccination to boost the immune response.
CanSino determined that the medium-dosage had a safer profile, which led the company to use the medium-dose in Phase 3 testing. Starting in August of 2020, CanSino is estimated to recruit over 40,000 participants on a global scale to test the efficacy and reactogenicity of the Adn-nCoV. Furthermore, an outside company, NPO Petrovax, is testing the efficacy and reactogenicity of Adn-nCoV on a smaller scale of 500 participants.
Gamaleya Research Institute
Gamaleya Research Institute (GRI) has designed a two-series vaccine, Gam-COVID-Vac (nicknamed Sputnik V), that utilizes the Adenovirus Type 26 (rAd26-S) in the first round and Adenovirus Type 5 (rAd5-S) in the second round as vectors for the SARS-CoV-2 spike protein gene. This mechanism is similar to other COVID-19 vaccine candidates, such as AstraZeneca, CanSino Biologics, and Johnson&Johnson.
GRI began round 1 of Phase 1/2 testing in June of 2020 in a non-randomized, open experiment. Healthy adults either received rAd26-S or rAd5-S on day 0 with close safety of each component for 28 days. In round 2 of Phase 1/2, participants received rAd26-S on day 0 and received rAd5-S on day 21. Common adverse side effects only extended to mild or moderate severity. Results indicated strong immune response and production of neutralizing antibodies of SARS-CoV-2 spike protein.
Phase 2 testing was an extension of Phase 1/2 where the study is non-randomized and open in the testing of Sputnik V on participants 60 years or older. The clinical began mid October 2020 with the enrollment of over 100 participants. Two Phase 3 clinical trials began in September 2020, one is large scale (40,000 participants) and the other is small (100 participants). In general, the experiments are randomized, double-blind, and placebo controlled.
It’s important to note that in early August of 2020, Russian regulators officially approved Gam-COVID-Vac. Within the scientific community, this decision came with protests as it is believed to be a premature decision, referencing the absence of the initiation and results of a Phase 3 clinical trial. Moreover, the Phase 1/2 trial was non-randomized, nor placebo controlled while only enrolling 38 healthy participants.
Additional Vaccines
According to the World Health Organization, there are 32 other COVID-19 vaccine candidates that are in earlier Phases of clinical trials or have yet to start a 3rd Phase. The above 8 candidates are the front runners. However, the other companies still have a stake in the race for a COVID-19 vaccine as trials continue to develop. Below will be brief information on companies on their vaccine type and Phase level.
Anhui Zhifei Longcom Biopharmacuetical (AZLB)
AZLB utilized a protein subunit from SARS-CoV-2 that works in collaboration with an adjuvant. This extra ingredient assists the body in creating a stronger immune response. The company has completed animal testing and has since moved to Phase 1 and Phase 2 testing, of which both have no final results.
Curevac has designed a vaccine that utilizes the mRNA that corresponds to a SARS-CoV-2 protein in order to instruct human cells to make the protein and allow the immune response to create an appropriate response. mRNA vaccines eliminate the risk of pathogenic particles from entering the body. Curevac is in the middle of Phase 1 and Phase 2 testing, where neither has final results.
Wuhan Institute of Biological Products (WIBP)
WIBP has developed a vaccine that includes an inactivated form of the SARS-CoV-2 virus. This type of vaccine is similar to Sinovac. The developer has posted interim results for the Phase 1/2 clinical trials. Although the vaccine candidate is in Phase 3 testing, information and data on the vaccine and results of trials was very limited.
Beijing Institute of Biological Products (BIBP)
BIBP has developed a vaccine that includes an inactivated form of the SARS-CoV-2 virus, similar to WIBP and Sinovac. Similarly, again, BIBP is in Phase 3 testing, yet hasn’t posted any results from previous clinical trials. Information and data on the candidate and the trial results were very limited.
Vaxart has designed a vaccine that utilizes Adenovirus Type 5 as a vector. However, the interesting part of the company’s design is that the vaccine is distributed orally rather than through a serum and needle. Vaxart is only in the Phase 1 testing without any posted results. Even if the company is not the first COVID-19 vaccine, the uniqueness of an oral vaccination could make it more accessible to poorer and isolated communities.
*For access to other vaccine candidates in earlier clinical Phases, visit this World Health Organization website that includes a brief document which discusses basic information about each vaccine and shares links to specifics of their clinical trials.
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