Here are the most promising coronavirus vaccine candidates out there

Here are the most promising coronavirus vaccine candidates out there

Here are the most promising coronavirus vaccine candidates out there

By Yasemin Saplakoglu – Livescience.com 25 Sept 2020

Vaccine syringes. (Image: © Westend61 via Getty Images)

Editor’s Note: This story was updated on Sept. 25 to to include:

— Johnson & Johnson began phase 3 trials of its candidate vaccine

— The University of Oxford/AstraZeneca began phase 3 trials in the U.S. and briefly paused/resumed their trials to investigate an unexplained illness. 

— a section on Novavax. The company began phase 3 trials in the U.K.

— Sinovac’s results from a phase 1/phase 2 trial on elderly participants

Using materials from weakened cold viruses to snippets of genetic code, scientists around the world are creating dozens of unique vaccine candidates to fight the novel coronavirus — and they’re doing it at unprecedented speeds.

Over seven months after the World Health Organization (WHO) first alerted the world to a mysterious cluster of pneumonia cases in Wuhan, China, 187 candidate vaccines are in development to prevent the coronavirus that caused the disease (called COVID-19), according to WHO. Most of the candidate vaccines are in preclinical stages, meaning they are still being tested on animals or in the lab, but 38 of them have reached human trials. 

Such clinical trials are broken up into three to four stages, with earlier stages (phase 1/phase 2) examining the safety, dosage, and possible side effects and efficacy (how well it works at fighting the pathogen) of the candidate vaccine in a small group of people, according to the Food and Drug Administration (FDA). The key to getting a candidate vaccine approved, however, is showing promising results in the more advanced phase 3 trial. 

Related: Coronavirus live updatesCLOSE

In phase 3 trials, researchers test the efficacy of the vaccine, while monitoring for adverse reactions in hundreds to thousands of volunteers. The FDA then approves the vaccine if trials show it is safe and effective, and the vaccine’s benefits outweigh its risks, according to the Centers for Disease Control and Prevention (CDC). Five coronavirus vaccine candidates have started recruiting for, or are undergoing, phase 3 trials, according to WHO. Here are the most promising of those candidates:

University of Oxford/AstraZeneca

The vaccine currently called ChAdOx1 nCoV-19, popularly known as the Oxford vaccine, is being developed by the British university in collaboration with pharmaceutical company AstraZeneca. A phase 3 clinical trial that’s expected to enroll around 30,000 adults began in the U.S. on Aug. 31, according to a statement from the National Institutes of Health. There are also phase 3 trials for ChAdOx1 nCoV-19 underway in the U.K. and other countries. 

On Sept. 6, AstraZeneca paused its trials after a participant — a woman in the U.K. — showed neurological symptoms often associated with transverse myelitis, a condition in which the spinal cord becomes inflamed, according to a previous Live Science report. But it wasn’t clear if the unexplained illness was due to the vaccine or occured in the participant by chance. The trials resumed a couple of days later, after the UK’s Medicines Health Regulatory Authority said it was safe to continue, according to CNBC.

The vaccine is made from a weakened version of a common cold virus, called an adenovirus, that infects chimpanzees. Researchers genetically altered the virus so that it couldn’t replicate in humans and added genes to code for the so-called spike proteins that the coronavirus uses to infect human cells. In theory, the vaccine will teach the body to recognize these spikes, so that when a person is exposed, the immune system can destroy it, according to a previous Live Science report

Researchers previously tested this vaccine in rhesus macaque monkeys and found that it did not prevent the monkeys from becoming infected when deliberately exposed to the coronavirus, but did prevent them from developing pneumonia, suggesting that it was partially protective, according to a study published May 13 to the preprint database BioRxiv.

In April, researchers began testing the vaccine on people and published early results from their phase 1 and still-ongoing phase 2 trials on July 20 in the journal The Lancet. The vaccine didn’t cause any serious adverse effects in participants but did prompt some mild side effects, such as muscle ache and chills. The vaccine spurred the immune system to produce SARS-CoV-2-specific T-cells — a group of white blood cells important in the fight against pathogens — and neutralizing antibodies, or molecules that can latch onto the virus and block it from infecting cells, according to the report.

Phase 3 trials have already begun in Brazil and will enroll up to 5,000 volunteers. Another phase 3 trial is expected to enroll an additional 10,500 people in the U.K. and 30,000 in the U.S., according to the Oxford vaccine trial webpage and The New York Times. The team at Oxford has also expressed interest in conducting challenge studies on humans, meaning they would deliberately infect low-risk volunteers with the virus, either alongside phase 3 trials or after they are complete, according to The Guardian.

The U.S. Department of Health and Human Services (HHS) announced that it would give up to $1.2 billion to AstraZeneca to accelerate the vaccine development process and to help the company manufacture at least 300 million doses of the vaccine — if it proves safe and effective — as early as October 2020, according to a statement. This is part of the Trump administration’s Operation Warp Speed, an initiative that aims to deliver 300 million doses of a safe and effective vaccine by January of 2021, according to HHS.

Sinovac Biotech

Another candidate vaccine, called CoronaVac , being developed by Beijing-based Sinovac Biotech, protected rhesus macaque monkeys from infection with the novel coronavirus, according to a study published July 3 in the journal Science. The company, having already shown the vaccine to be safe and effective in early clinical trials, is recruiting for a phase 3 clinical trial with 8,870 participants in Brazil, according to clinicaltrials.gov.

This vaccine is made up of an inactivated version of the SARS-CoV-2 virus. Inactivated vaccines are the dead version of the pathogen that causes the disease (as opposed to weakened viruses which are live vaccines), according to the U.S. Department of Health and Human Services (HHS). Inactivated viruses such as the flu vaccine or the hepatitis A vaccine, are typically not as protective as live vaccines and might require booster shots over time, according to the HHS. In contrast, the Oxford vaccine is a weakened form of a live vaccine, which can create long-lasting immune responses but tends to be riskier for people with weakened immune systems or other health problems, according to the HHS.

Sinovac began phase 1/phase 2 trials (involving 743 healthy adults) in April in the Jiangsu province of China. They gave participants two doses of the vaccine, two weeks apart, and reported that the vaccine didn’t cause any serious adverse events, according to a statement. Study authors also said more than 90% of participants had developed neutralizing antibodies to the vaccine two weeks after receiving the second dose. However, their results have only been reported in a press release and haven’t yet been published in a peer-reviewed journal. The company is now conducting a phase 2 trial on elderly adults and will later conduct one on children and adolescents, according to another statement. Sinovac previously used the same technology to create approved vaccines for hepatitis A, hepatitis B and swine flu, avian flu and the virus that causes hand, foot and mouth disease, according to STAT News

On Sept. 9, Sinovac reported promising early results from their phase 1/phase 2 clinical trial on older volunteers, according to a statement. The trial involved 421 healthy volunteers between the ages of 60 and 89. The vaccine didn’t cause any serious adverse reactions and it was well tolerated, the company said in the statement. These participants developed antibody levels comparable to the adult group ages 18 to 59, according to the statement; the findings have not yet been published in a peer-reviewed journal.

China has approved this vaccine for emergency use (along with two other vaccines developed by Sinopharm). About 90% of Sinovac’s employees and their families have taken the experimental vaccine under China’s emergency use program, Reuters reported on Sept. 6.

Moderna/National Institute of Allergy and Infectious Diseases

This candidate vaccine (mRNA-1273), developed by U.S. biotech company Moderna and the National Institute of Allergy and Infectious Diseases (NIAID), was the first to be tested on humans in the U.S., according to a previous Live Science report

Moderna’s vaccine relies on a technology that hasn’t been used in any approved vaccines to date: a piece of genetic material called messenger RNA (mRNA). Traditional vaccines are made up of weakened or inactive viruses, or proteins of those viruses, to trigger an immune response; mRNA vaccines, on the other hand, are made up of genetic material that teaches cells to build these viral proteins themselves (in this case, the coronavirus’ spike protein). Both traditional and mRNA vaccines trigger an immune response in the body such that if a person is naturally exposed to the virus, the body can quickly recognize and fight it. 

These mRNA vaccines have several advantages, including being quicker and easier to manufacture than traditional vaccines, which can take time to develop because scientists have to grow and inactivate entire pathogens or their proteins, according to National Geographic. mRNA vaccines might also be more durable against pathogens that tend to mutate, such as coronaviruses and flu viruses. However, mRNA vaccines can cause adverse reactions in the body; these types of vaccines also have problems with stability, breaking down quite quickly, which might limit the strength of immunity, according to National Geographic.

mRNA vaccines have shown to be “a promising alternative” to traditional vaccines, but “their application has until recently been restricted by the instability and inefficient” delivery into the body, a group of researchers reported in a 2018 review published in the journal Nature Reviews Drug Discovery. “Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans.”

On July 14, Moderna published promising early results from a phase 1 trial consisting of 45 participants in The New England Journal of Medicine. Participants were divided into three groups and given a low, medium or high dose of the vaccine. After receiving two doses of the vaccine, all participants developed neutralizing antibodies at levels above the average of those found in recovered COVID-19 patients, Live Science reported

The vaccine appeared safe and generally well-tolerated, but more than half of the participants had some side effects (similar to side effects that can happen from the annual flu shot) including fatigue, chills, headache, muscle aches and pain at the injection site. Some participants in the middle- and high-dose groups experienced a fever after the second injection. One person who received the highest dose experienced a “severe” fever, nausea, lightheadedness and an episode of fainting, according to the report. But this participant felt better after a day and a half. Such high doses won’t be given to participants in upcoming trials.

Moderna’s phase 2 trial is still ongoing and on July 27, the company started its phase 3 trial in the U.S., according to a Live Science report. The trial is expected to enroll about 30,000 participants by the end of the summer — and the first results from the trial might be available by November, according to the report.

In April, the HHS, under Operation Warp Speed, committed to spending up to $483 million for the accelerated development of Moderna’s vaccine.

On July 28, scientists published a new in The New England Journal of Medicine detailing how Moderna’s vaccine induced a strong immune response in rhesus macaque monkeys. After being given a 10 or 100 μg dose of the vaccine and then a second dose two weeks later (some were not given a vaccine and served as a comparison point), the monkeys were “challenged” or exposed to the coronavirus at week 8. The researchers found that the monkeys developed a strong immune response to the virus, as their immune systems produced both neutralizing antibodies and T cells. Two days after the monkeys were exposed to the coronavirus, the researchers could not detect any viral replication in the nose or lungs, suggesting that the vaccine protected against early infection. (This is in contrast to the University of Oxford study conducted in monkeys, which seemed to prevent the monkeys from developing pneumonia, but didn’t prevent them from getting infected with the novel coronavirus.)

CanSino Biologics/Beijing Institute of Biotechnology

CanSino Biologics, in collaboration with the Beijing Institute of Biotechnology, developed a candidate vaccine using a weakened adenovirus. Unlike the Oxford vaccine, which relies on an adenovirus that infects chimpanzees, CanSino Biologics is using an adenovirus that infects humans. 

Along with Moderna, this group also published results from their phase 2 trial on July 20 in the journal The Lancet. The trial, which was conducted in Wuhan (where the first coronavirus cases emerged), involved 508 participants who were randomly assigned to receive either one of two different doses of the vaccine or a placebo. 

This study also didn’t find serious adverse events, though some reported mild or moderate reactions including fever, fatigue and injection site pain. Around 90% of the participants developed T-cell responses and about 85% developed neutralizing antibodies, according to the study. 

“The results of both studies augur well for phase 3 trials, where the vaccines must be tested on much larger populations of participants to assess their efficacy and safety,” Naor Bar-Zeev and William J Moss, both part of John Hopkins’ International Vaccine Access Center, wrote in an accompanying commentary in The Lancet referring to this study and the Oxford vaccine study published in the same journal. “Overall, the results of both trials are broadly similar and promising.” 

They are now looking to conduct a phase 3 trial outside of China, according to Reuters. In June, CanSino’s coronavirus vaccine was given approval to be used in China’s military, according to Reuters

Sinopharm

The state-owned China National Pharmaceutical Group (Sinopharm)’s candidate vaccine is an inactivated form of SARS-CoV-2. On Aug. 13, the company published data from its phase 1 and phase 2 clinical trials in the journal JAMA. In the phase 1 trial, 96 healthy adults were randomly assigned to receive either a low, medium or high dose of the vaccine or to receive aluminum hydroxide as a placebo. They were given second and third doses of the vaccine (or the placebo) after 28 days and 56 days, respectively. 

The researchers found that the vaccine triggered their bodies to produce neutralizing antibodies. In the participants who received the placebo, 12.5% had adverse reactions. In those who received low, medium and high dose vaccines, 20.8%, 16.7% and 25% had mild adverse reactions, respectively, according to the study. In the phase 2 trial, 224 adults were given a medium dose or a placebo and then a second shot either 14 days or 21 days after the first. Again, the participants developed neutralizing antibodies and reported some mild adverse reactions. The most common adverse reaction was pain at the injection site, and then mild fever. “No serious adverse reactions were noted,” the authors wrote.

The company has already begun its phase 3 trial in Abu Dhabi, which will recruit up to 15,000 people, according to Reuters. The participants will receive one of two vaccine strains or a placebo, according to Reuters. The company also launched phase 3 trials in Peru and Morocco, according to Reuters

Sinopharm is testing a second vaccine developed by the Beijing Institute of Biological Products in a phase 3 trial in the United Arab Emirates and Argentina. 

Hundreds of thousands of Chinese citizens have already been vaccinated by one of two of Sinopharm’s vaccines under an emergency use program, according to Vox.  The United Arab Emirates granted emergency approval on Sept. 14 for Sinopharm’s coronavirus vaccine for frontline healthcare workers (it’s not clear if they approved both or one of them), according to Reuters

Pfizer/BioNTech/Fosun Pharmaceutical

Pfizer and German biotechnology company BioNTech are, like Moderna, developing a vaccine that uses messenger RNA to prompt the immune system to recognize the coronavirus.

On July 27, Pfizer and BioNTech announced the start of their phase 2/phase 3 trials that will enroll up to 30,000 participants and be conducted in around 120 sites around the world, including in the U.S. If the vaccine is shown safe and effective in these trials, the companies say they will “seek regulatory review” as early as October; if the vaccine is approved or authorized, they will supply up to 100 million doses by the end of 2020 and around 1.3 billion doses by the end of 2021, according to the statement. On Sept. 12, the companies announced they submitted an “amended protocol” to the U.S. Food and Drug Administration to expand their phase 3 trial to up to 44,000 people.

The vaccine didn’t cause any serious adverse events and could spur an immune response, according to early phase 1/phase 2 data released to the preprint database medRxiv on July 1 and that hasn’t yet been peer-reviewed. The study involved 45 patients who were given one of three doses of either the candidate vaccine or a placebo. None of the patients had serious side effects, but some developed side effects such as fevers (75% in the highest dose group), fatigue, headaches, chills, muscle pains and joint pain. 

The researchers found that the vaccine prompted the immune system to make neutralizing antibodies at levels 1.8 to 2.8 times higher than those found in recovered patients, according to the study. Later, Pfizer announced new results (in a press release, so the findings aren’t peer-reviewed) that the vaccine also prompted the production of T-cells specific to the novel coronavirus. 

This week, the Trump administration announced a $1.95 billion contract with Pfizer and BioNTech to produce at least 100 million doses of their vaccine by the end of the year if it proves to be safe and effective (with up to 500 million doses more as required). Americans would receive the vaccine for free, according to The New York Times. Previously, the two companies announced an agreement with the U.K. for 30 million doses of the vaccine candidate if it works and is approved, according to a statement

Pfizer is planning for a large-scale phase 3 trial to start this month and regulatory review for as early as October, according to the Times.

Johnson & Johnson’s Janssen Pharmaceutical Companies

Johnson & Johnson began phase 3 trials in the U.S. on Sept. 23., according to a statement from the company. The trial will enroll up to 60,000 volunteers across the U.S., Brazil, Chile, Columbia, Mexico, Peru, Philippines, South Africa and the Ukraine, according to ClinicalTrials.gov. The initiation of this trial follows “positive interim results,” regarding safety and efficacy from the phase 1/phase 2 clinical trial, which has been submitted to medRxiv and “are due to be published online imminently,” the company wrote in the statement. If the vaccine proves to be safe and effective, the company “anticipates the first batches of a COVID-19 vaccine to be available for emergency use authorization in early 2021,” according to the statement.

Johnson & Johnson’s Janssen experimental COVID-19 vaccine, called Ad26, is developed from a weakened adenovirus and is given to volunteers as a single dose. The company is planning to conduct another phase 3 trial, in collaboration with the U.K. government, to test two doses, according to CNN. This type of vaccine is called a vector-based vaccine because it uses a weakened virus (a vector) to deliver information about the pathogen to the body to spur the immune response. In this case, the weakened adenovirus expresses the SARS-CoV-2 “spike” protein. Janssen is using the same technology it used to develop its Ebola vaccine

Researchers reported on July 30 in the journal Nature that a single shot of the Ad26 vaccine protected rhesus macaques from infection with SARS-CoV-2. In this study, the scientists tested seven slightly varying types of Ad26 vaccine prototypes and identified the one that produced the highest number of neutralizing antibodies. After receiving the chosen variant, the monkeys were then exposed to the coronavirus. Six out of seven monkeys that were given this prototype vaccine, calledAd26.COV2.S, and then exposed to the coronavirus showed no detectable virus in the lower respiratory tract and one showed very low levels in its nose, according to the statement. 

Johnson & Johnson’s Phase 1/2 clinical trial of Ad26.COV2.S enrolled around 1,045 healthy participants between the ages of 18 and 55 and those over 65. Johnson & Johnson recently announced a $1 billion agreement with the U.S. government to deliver 100 million doses of the vaccine in the U.S. if it receives approval or emergency use authorization from the U.S. Food and Drug Administration, according to a statement

Novavax

U.S.-based vaccine development company Novavax is developing a candidate coronavirus vaccine called NVX-CoV2373. Called a “recombinant nanoparticle vaccine,” it’s made up of several SARS-CoV-2 spike proteins that are combined in a nanoparticle along with an immune-boosting compound called an adjuvant, according to The New York Times.

The company, which has not brought a vaccine to market in it’s 33-year-history, has made a $1.6 billion deal with the U.S. government under Operation Warp Speed, according to the Times. On Sept. 2, early, promising results from Novavax’s phase 1/phase 2 trials were published in The New England Journal of Medicine.

The trials involved 131 healthy adults: eighty-three of the participants received the vaccine with the adjuvant; 25 received the vaccine without the adjuvant; and 23 received the placebo. The participants were given two doses of the vaccine 21 days apart. “No serious adverse events were noted,” the researchers wrote. One participant had a mild fever that lasted for a day, according to the paper.

Thirty-five days after the initial dose, participants who received the vaccine had immune responses that exceeded those in patients who recovered from COVID-19. All of the participants developed neutralizing antibodies at levels of four to six times greater than the average developed by recovered patients, according to CNN. In 16 participants, who were randomly tested, the vaccine seemed to generate T-cell responses (T cells are a group of white blood cells important in the fight against pathogens). “The addition of adjuvant resulted in enhanced immune responses,” the authors wrote. 

Based on these safety results from phase 1, the company has begun the phase 2 trial of the study. The company has also begun a separate phase 2 study in South Africa, testing their candidate COVID-19 vaccine on both HIV-negative and HIV-positive volunteers. On Sept. 24, Novavax announced that it started its phase 3 testing of the vaccine in the United Kingdom and will enroll up to 10,000 volunteers. 

Originally published on Live Science.

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