A Phase 2 clinical trial evaluating various additional COVID-19 booster shots has begun enrolling adult participants in the United States. The trial aims to understand if different vaccine regimens—prototype and variant vaccines alone and in combinations—can broaden immune responses in adults who already have received a primary vaccination series and a first booster shot. The study, known as the COVID-19 Variant Immunologic Landscape (COVAIL) trial, is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
“We are looking beyond the Omicron variant to determine the best strategy to protect against future variants,” said NIAID Director Anthony S. Fauci, M.D. “This trial will help us understand if we can use prototype and variant vaccines alone or together to shift immune responses to cover existing and emerging COVID-19 variants.”
Despite waning protection against infection and mild illness during the Omicron wave, COVID-19 vaccines available in the United States so far have maintained durable protection against severe COVID-19. However, NIAID is preparing for the possibility of future variants evading protection against currently available COVID-19 vaccines.
COVID-19 vaccine manufacturers can adjust prototype vaccines to target specific variants, a process similar to how manufacturers update seasonal influenza vaccines every year to target circulating strains. However, predicting if, when and where new COVID-19 variants will emerge and how they will affect the population, remains challenging. Studies(link is external) indicate that Omicron has a combination of mutations that make it substantially different from prior SARS-CoV-2 variants. Should a new variant emerge that more closely resembles ancestral SARS-CoV-2 or, for example, the Delta variant, an Omicron-specific vaccine may not offer substantial protection. An individual’s response to booster shots may also be impacted by their history of prior infection and vaccination, or both, and what type of COVID-19 vaccines they received.
Vaccine manufacturers have previously studied some variant vaccine candidates and are currently conducting clinical trials of Omicron-specific vaccines. The COVAIL trial will gather data on the immune responses induced by prototype vaccines and variant vaccine candidates—including bivalent vaccines, which target two SARS-CoV-2 variants—to inform booster shot recommendations.
The first stage of this trial is being conducted in collaboration with Moderna, Inc., based in Cambridge, Massachusetts, and Moderna is manufacturing the study vaccines that will be administered. The trial will be adapted to enroll more participants to evaluate additional vaccine platforms and variant vaccines from other manufacturers as needed to further inform public health decisions. Participants will be monitored for symptoms and adverse events following vaccination and will be asked to return to the clinic during set times over the course of 12-14 months to provide blood samples. Investigators will evaluate the samples in the laboratory to measure and characterize immune responses to SARS-CoV-2 strains. Investigators aim to have initial findings available by August 2022.
Nadine Rouphael, M.D., director of the Hope Clinic at the Emory Vaccine Center in Atlanta, and Angela Branche, M.D., associate professor of medicine at the University of Rochester Medical Center in New York, are leading the trial. Site investigators at 24 clinics are enrolling 600 participants 18 years and older who already have received a primary COVID-19 vaccination series and booster shot. Participants are randomly assigned to one of six vaccine regimens:
The home and point-of-care testing platforms target the need for high-performance, low-cost home tests and point-of-care tests that can potentially detect multiple respiratory infections. These projects are part of the RADx Tech program, which involves an intensive concept viability “shark-tank”-like assessment conducted by a panel of technical, regulatory and business experts. The awards support the development, validation, scale-up and manufacturing with the goal of bringing needed tests to the market as early as this year.
“These technologies represent important innovations to address the need for ready access to rapid, low-costs tests everywhere in the country, including in every home,” said Bruce J. Tromberg, Ph.D., director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and lead for RADx Tech. “The potential to test simultaneously for multiple types of infection at the point-of-care, is a new frontier that we hope to advance and could be a major step toward transforming U.S. healthcare.”
The new awards are in addition to 33 that NIH previously disbursed through its technology development program. The RADx Tech program has resulted in 32 U.S. Food and Drug Administration emergency use authorizations (EUAs), including supporting the first home test EUA. Companies supported by the RADx program that achieved an EUA have contributed over 840 million tests to the U.S. market since fall of 2020.
Results from a Phase 3 clinical trial enrolling 29,960 adult volunteers in the United States and Mexico show that the investigational vaccine known as NVX-CoV2373 demonstrated 90.4% efficacy in preventing symptomatic COVID-19 disease.
The candidate showed 100% protection against moderate and severe disease. In people at high risk of developing complications from COVID-19 (people 65 years or older and people under age 65 with certain comorbidities or with likely regular exposure to COVID-19), the vaccine showed 91.0% efficacy in preventing symptomatic COVID-19 disease.
Safety data indicate the investigational vaccine was generally well-tolerated. Mild-to-moderate injection site pain and tenderness were the most common local symptoms among participants, and fatigue, headache and muscle pain lasting less than two days were the most common systemic symptoms.
Novavax, Inc., of Gaithersburg, Maryland, developed the investigational vaccine and led the clinical trial known as PREVENT-19(link is external). The Biomedical Advanced Research and Development Authority (BARDA), a component of the HHS Office of the Assistant Secretary for Preparedness and Response, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, provided funding support for the trial as part of the federal COVID-19 response.
The PREVENT-19 trial began in late December 2020 and enrolled adult volunteers at 119 study sites, including those in the NIAID-supported COVID-19 Prevention Network (CoVPN)(link is external). Participants were randomly assigned to receive two shots, 21 days apart, of either the investigational vaccine or a saline placebo. Randomization occurred in a 2:1 ratio with two volunteers receiving NVX-CoV2373 for each one who received placebo. Because the trial was blinded, neither investigators nor participants knew who received the candidate vaccine.
PREVENT-19 was designed to evaluate whether NVX-CoV2373 can prevent symptomatic COVID-19 disease seven or more days after the second injection relative to placebo. The results shared today are based on 77 cases of symptomatic COVID-19 that investigators observed among trial participants from January 25 through April 30, 2021. Investigators recorded 63 cases among the approximately 10,000 participants who received placebo and 14 cases among the approximately 20,000 participants who received the investigational vaccine. Of the 63 COVID-19 cases in the placebo group, investigators classified 10 as moderate and four as severe. There were no cases of moderate or severe disease in the investigational vaccine group.
NVX-CoV2373 is a subunit vaccine made from a stabilized form of the coronavirus spike protein using the company’s recombinant protein nanoparticle technology. The purified protein antigens in the vaccine cannot replicate or cause COVID-19. The vaccine also contains a proprietary adjuvant, MatrixM™. Adjuvants are additives that enhance desired immune system responses to vaccine. NVX-CoV2373 is administered by injection in liquid form and can be stored, handled and distributed at above-freezing temperatures (35° to 46°F.) A single vaccine dose contains 5 micrograms (mcg) of protein and 50 mcg of adjuvant. The vaccine is administered as two intramuscular injections 21 days apart. The technology used for this vaccine was developed under a long-standing contract with the Department of Defense.
An investigational COVID-19 vaccine developed by Janssen Pharmaceuticals appears to be safe and effective at preventing moderate and severe COVID-19 in adults, according to an interim analysis of Phase 3 clinical data conducted Jan. 21.
The vaccine, called Ad.26.COV2.S or JNJ-78436725, requires only a single injection and can be stored in a refrigerator for months.
The interim analysis assessed 468 cases of symptomatic COVID-19 among 44,325 adult volunteers in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the United States. The investigational vaccine was reportedly 66% effective at preventing the study’s combined endpoints of moderate and severe COVID-19 at 28 days post-vaccination among all volunteers, including those infected with an emerging viral variant. Moderate COVID-19 was defined as laboratory-confirmed SARS-CoV-2 plus either one of the following: evidence of pneumonia; deep vein thrombosis; difficulty breathing; abnormal oxygen saturation or a respiratory rate equal to or greater than 20; or two or more signs or symptoms suggestive of COVID-19, such as cough, sore throat, fever or chills. Severe COVID-19 was defined as laboratory-confirmed SARS-CoV-2 plus evidence of clinical signs at rest indicative of severe systemic illness, respiratory failure, shock, significant organ dysfunction, hospital intensive care unit admission or death.
Geographically, the level of protection for the combined endpoints of moderate and severe disease varied: 72% in the United States; 66% in Latin American countries; and 57% in South Africa, 28 days post-vaccination. The investigational vaccine was reportedly 85% effective in preventing severe/critical COVID-19 across all geographical regions. No deaths related to COVID-19 were reported in the vaccine group, while 5 deaths in the placebo group were related to COVID-19. Overall, there were 16 deaths in the placebo group, and 3 deaths in the vaccine group.
The Janssen Pharmaceutical Companies of Johnson & Johnson developed the experimental vaccine and served as the regulatory sponsor of the Phase 3 clinical study known as ENSEMBLE. Janssen; the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health; and the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response, funded approximately 55% of the trial through a cost-sharing agreement. The ENSEMBLE trial, which began Sept. 23, 2020, is being conducted as part of the federal COVID-19 response.
The Janssen vaccine is a recombinant vector vaccine that uses a human adenovirus to express the SARS-CoV-2 spike protein. SARS-CoV-2 is the virus that causes COVID-19. Adenoviruses are a group of viruses that cause infections in the respiratory and gastrointestinal tracts; the adenovirus vector used in the experimental vaccine has been modified, so that it can no longer replicate in humans and cause illness. In developing the vaccine, Janssen employed the same vector used in the first dose of its prime-boost vaccine regimen against Ebola virus disease (Ad26 ZEBOV and MVN-BN-Filo), developed under a long-standing partnership with BARDA and granted marketing authorization by the European Commission in July 2020. Unlike the two COVID-19 vaccines currently authorized by the U.S. Food and Drug Administration for emergency use (Pfizer and Moderna vaccines), the Janssen investigational vaccine requires only a single vaccination.
NIAID-Led Study of mRNA Vaccine Supports Advance to Phase 3 Human Trials
Two doses of an experimental vaccine to prevent coronavirus disease 2019 (COVID-19) induced robust immune responses and rapidly controlled the coronavirus in the upper and lower airways of rhesus macaques exposed to SARS-CoV-2, report scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. SARS-CoV-2 is the virus that causes COVID-19.
The candidate vaccine, mRNA-1273, was co-developed by scientists at the NIAID Vaccine Research Center and at Moderna, Inc., Cambridge, Massachusetts. The animal study results published online today in the New England Journal of Medicine complement recently reported interim results from an NIAID-sponsored Phase 1 clinical trial of mRNA-1273. The candidate mRNA-1273 vaccine is manufactured by Moderna.
In this study, three groups of eight rhesus macaques received two injections of 10 or 100 micrograms (µg) of mRNA-1273 or a placebo. Injections were spaced 28 days apart. Vaccinated macaques produced high levels of neutralizing antibodies directed at the surface spike protein used by SARS-CoV-2 to attach to and enter cells. Notably, say the investigators, animals receiving the 10-µg or 100-µg dose vaccine candidate produced neutralizing antibodies in the blood at levels well above those found in people who recovered from COVID-19.
The experimental vaccine also induced Th1 T-cell responses but not Th2 responses. Induction of Th2 responses has been associated with a phenomenon called vaccine-associated enhancement of respiratory disease (VAERD). Vaccine-induced Th1 responses have not been associated with VAERD for other respiratory diseases. In addition, the experimental vaccine induced T follicular helper T-cell responses that may have contributed to the robust antibody response.
Four weeks after the second injection, all the macaques were exposed to SARS-CoV-2 via both the nose and the lungs. Remarkably, after two days, no replicating virus was detectable in the lungs of seven out of eight of the macaques in both vaccinated groups, while all eight placebo-injected animals continued to have replicating virus in the lung. Moreover, none of the eight macaques vaccinated with 100 µg of mRNA-1273 had detectable virus in their noses two days after virus exposure. This is the first time an experimental COVID-19 vaccine tested in nonhuman primates has been shown to produce such rapid viral control in the upper airway, the investigators note. A COVID-19 vaccine that reduces viral replication in the lungs would limit disease in the individual, while reducing shedding in the upper airway would potentially lessen transmission of SARS-CoV-2 and consequently reduce the spread of disease, they add.
The world’s biggest COVID-19 vaccine study got underway Monday with the first of 30,000 planned volunteers helping to test shots created by the U.S. government — one of several candidates in the final stretch of the global vaccine race.
There’s still no guarantee that the experimental vaccine, developed by the National Institutes of Health and Cambridge-based Moderna Inc., will really protect.
The needed proof: Volunteers won’t know if they’re getting the real shot or a dummy version. After two doses, scientists will closely track which group experiences more infections as they go about their daily routines, especially in areas where the virus still is spreading unchecked.
“Unfortunately for the United States of America, we have plenty of infections right now” to get that answer, NIH’s Dr. Anthony Fauci recently told The Associated Press.
Moderna said the vaccination was done in Savannah, Georgia, the first site to get underway among more than seven dozen trial sites scattered around the country.
Several other vaccines made by China and by Britain’s Oxford University earlier this month began smaller final-stage tests in Brazil and other hard-hit countries.
But the U.S. requires its own tests of any vaccine that might be used in the country and has set a high bar: Every month through fall, the government-funded COVID-19 Prevention Network will roll out a new study of a leading candidate — each one with 30,000 newly recruited volunteers.
The massive studies aren’t just to test if the shots work — they’re needed to check each potential vaccine’s safety. And following the same study rules will let scientists eventually compare all the shots.
Next up in August, the final study of the Oxford shot begins, followed by plans to test a candidate from Johnson & Johnson in September and Novavax in October — if all goes according to schedule. Pfizer Inc. plans its own 30,000-person study this summer.
That’s a stunning number of people needed to roll up their sleeves for science. But in recent weeks, more than 150,000 Americans filled out an online registry signaling interest, said Dr. Larry Corey, a virologist with the Fred Hutchinson Cancer Research Institute in Seattle, who helps oversee the study sites.
“These trials need to be multigenerational, they need to be multiethnic, they need to reflect the diversity of the United States population,” Corey told a vaccine meeting last week. He stressed that it’s especially important to ensure enough Black and Hispanic participants as those populations are hard-hit by COVID-19.
It normally takes years to create a new vaccine from scratch, but scientists are setting speed records this time around, spurred by knowledge that vaccination is the world’s best hope against the pandemic. The coronavirus wasn’t even known to exist before late December, and vaccine makers sprang into action Jan. 10 when China shared the virus’ genetic sequence.
Just 65 days later in March, the NIH-made vaccine was tested in people. The first recipient is encouraging others to volunteer now.
“We all feel so helpless right now. There’s very little that we can do to combat this virus. And being able to participate in this trial has given me a sense of, that I’m doing something,” Jennifer Haller of Seattle told the AP. “Be prepared for a lot of questions from your friends and family about how it’s going, and a lot of thank-you’s.”
That first-stage study that included Haller and 44 others showed the shots revved up volunteers’ immune systems in ways scientists expect will be protective, with some minor side effects such as a brief fever, chills and pain at the injection site. Early testing of other leading candidates have had similarly encouraging results.
If everything goes right with the final studies, it still will take months for the first data to trickle in from the Moderna test, followed by the Oxford one.
Governments around the world are trying to stockpile millions of doses of those leading candidates so if and when regulators approve one or more vaccines, immunizations can begin immediately. But the first available doses will be rationed, presumably reserved for people at highest risk from the virus.
“We’re optimistic, cautiously optimistic” that the vaccine will work and that “toward the end of the year” there will be data to prove it, Dr. Stephen Hoge, president of Moderna, told a House subcommittee last week.
Until then, Haller, the volunteer vaccinated back in March, wears a mask in public and takes the same distancing precautions advised for everyone — while hoping that one of the shots in the pipeline pans out.
“I don’t know what the chances are that this is the exact right vaccine. But thank goodness that there are so many others out there battling this right now,” she said.
AP photographer Ted Warren in Seattle contributed to this report.
There isn’t enough clinical research being done in Africa. Less than 2.5% of all clinical trials in the world are done on the continent. This is why South Africa’s involvement in one of the COVID-19 vaccine trials is so important. The country’s effort is being led by Professor Shabir Madhi. The Conversation Africa’s health and medicine editor Ina Skosana spoke to him about the process, and what can be expected. This is an edited version of a podcast, which you can listen to here.
How does the trial work?
The study that we embarked on in South Africa is for a vaccine that was developed by the Jenner Institute at the University of Oxford. It’s what is known as a non-replicating vector base COVID-19 vaccine.
The study came about when I reached out to the principal investigator at the University of Oxford whom I’ve known for over 20 years to find out if there was any interest on their part to include South Africa as part of the clinical development plan of the vaccine. The short answer was yes, provided we conducted the study on our own, including raising the funding to conduct the study.
The agreement with Oxford University preceded a subsequent agreement that they’ve entered into with AstraZeneca, the pharmaceutical company responsible for the further clinical development of the vaccine and future manufacturing. Pre-clinical studies of this vaccine candidate, including in non-human primates, have demonstrated initial evidence of the safety of this vaccine, as well as its ability to protect against COVID-19 disease.
Why South Africa?
The main reason is that the legacy of vaccines shows that they don’t necessarily work similarly across different populations. So if we want to be one of the early adopters, in terms of implementing vaccination against COVID-19 as part of our immunisation programme, we really need to generate data applicable to the local context.
A number of past vaccines have been shown to be highly efficacious in high income settings. But when they’ve gone on to be evaluated in low and middle income settings, they were found to be much less efficacious and, at times, not efficacious at all.
So if we want to make informed decisions at an early stage about whether these vaccines are going to be of benefit to people in South Africa, it’s critical that we undertake the clinical evaluation during the start of the entire programme, rather than at the latter stage. Waiting for results to come in from other studies would just lead to a lag in terms of the timing when vaccines would be introduced in South Africa as well as other low and middle income countries.
This has been the experience for many other life saving vaccines where it has taken between five and 20 years between their availability in high income countries and low middle income countries.
How are participants chosen for the trial?
Participation is completely voluntary.
Participants typically come to inquire about the study at clinics. We sit down with them and explain what the study is all about. What are the criteria for joining, what the expectations are of the volunteers because the study has quite intense expectations in terms of being able to come for regular visits. And they obviously need to be agreeable that when they do participate in the study, if they do develop signs and symptoms suggestive of COVID-19, that they would come forward to be investigated. This is critical for us to be able to determine whether this vaccine protects against COVID-19.
In addition, we would do some blood tests which ensures that they don’t have any sort of medical conditions that we would want to exclude.
If they’re found to be eligible, we randomly allocate them to one of two groups. Half will receive the vaccine, and the other half a control substance, which in our case, is a placebo. This is important for two reasons. The first is that it allows us to provide robust data in terms of the safety profile of the vaccine. And the control group enables us to determine whether the vaccine actually does have any impact in protecting against COVID-19.
Is there any reason people should be sceptical of the trial?
The short answer is no. The narratives that Africans are being used as guinea pigs is fundamentally incorrect. Rather a case of us wanting to generate robust scientific data to be able to make informed decisions about whether those vaccines actually do protect South Africans – and possibly Africans more generally – against developing COVID-19.
What are the next steps?
Right now we busy enrolling into the clinical trial. We’ve just reached the 200 mark out of the 2000 participants that we plan to enrol. We expect to have completed enrollment of all the volunteers over the next three to four weeks.
After that we will keep in touch with all of the participants at least every two weeks, including weekly SMS messages to determine whether or not experiencing any signs or symptoms of COVID-19. And if they are they will be asked to come in to be investigated to determine whether they are infected or not.
The endgame of the study is twofold. One is obviously to evaluate the safety of the vaccine, which is something that is ongoing almost on a daily basis.
The second part is that once we have about 42 individuals that have developed COVID-19 at least about a month after they’ve received the first dose of either the vaccine or the placebo we will then be able to do an analysis to determine whether the vaccine actually does protect against COVID-19. Specifically we will be testing if the vaccine efficacy is at least 60%; that is by being vaccinated your risk for developing COVID-19 will be reduced by at least 60% if not more.
We anticipate that we will probably be able to provide an answer as to whether this vaccine works and protects against COVID-19 by the end of November this year. In the worst case scenario it might take us a bit longer probably into the second quarter of next year.
What about managing expectations?
It’s very exciting to be involved in the sort of clinical development of the vaccine. But we need to be guarded in terms of our expectations as to what the result will be.
The fact that we’re embarking on a clinical trial doesn’t mean that we’re going to have a vaccine that’s going to protect against COVID-19.
Only about 10% of vaccines that go into clinical trials are eventually licensed for use. Right now there’ are approximately 200 vaccines that are being developed for COVID-19. It would be a huge accomplishment if, over the next 12 to 18 months, we are successful showing that even one out of every 20 (5%) of the vaccines that go into human studies are safe and provide some protection against COVID-19.
So even though there’s a huge amount of work taking place around vaccines, at least for the next 12 months the only tools that we’ve got available to us to try to protect people is adherence to physical distancing, the wearing of face masks in public spaces, avoiding mass gatherings, and making sure that you’re in adequately ventilated settings when in public spaces.
Anyone living in South Africa who is interested in participating in the study can e-mail firstname.lastname@example.org for more information.