Past research and ‘unlimited resources’ spur fast development of COVID-19 vaccines
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When scientists began working on solutions for the COVID-19 pandemic in early 2020, it seemed unlikely that a safe and effective vaccine would be available in a year, according to Paul A. Offit, MD.
Yet, by mid-December, the FDA had authorized two messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna for emergency use after researchers found they were more than 90% efficacious in late-stage trials — data now backed up by real-world evidence.
Source: Courtesy of Florian Krammer, PhD
“Certainly, no one would have predicted that these mRNA vaccines would have worked as well or been as safe as they are,” Offit, who heads the Vaccine Education Center at The Children’s Hospital of Philadelphia, told Infectious Disease News. “I’m sure you wouldn’t have been able to find one scientist on the planet who, a year ago, would have said these vaccines will be 95% effective overall against all disease, 95% effective in people over 65, effective in people with a variety of comorbidities, and be safe not only in preapproval trials of tens of thousands of people, but after they have been given to millions of people. I don’t think you could have devised a vaccine that appears to be more perfect. Whether that will also apply to other pathogens, we’ll see.”
A vaccine manufactured by Johnson & Johnson that uses an adenovirus vector became the third COVID-19 shot available in the United States in February.
Infectious Disease News spoke with Offit and other experts about how past successes in vaccine research and billions of dollars in public funds led to the development of these vaccines in record time, and what it could mean for vaccines against other diseases.
Set up for success
Offit has noted that the previous record for developing a vaccine was the mumps vaccine, which took about 4 years to become commercially available to the public.
Scientists were able to develop COVID-19 vaccines so quickly partly because of years of previous research focused on related viruses and faster ways to manufacture vaccines — namely nonvectored vaccines such as mRNA vaccines, experts said.
Unlike other vaccines, mRNA vaccines do not use a weakened or inactivated virus in order to trigger an immune response, the CDC noted. Instead, mRNA vaccines teach us to make a protein that triggers an immune response that produces antibodies, providing protection from real viruses.
Despite being a “newer” technology, researchers have been studying mRNA vaccines for decades, with interest in them only growing as researchers learned that the vaccines “can be developed in a laboratory using readily available materials,” allowing for a standardized process and faster development, the CDC said.
According to Dial Hewlett Jr., MD, FIDSA, medical director in the division of disease control at the Westchester (New York) County Department of Health, some of the technology for mRNA vaccines was developed in the study of Ebola vaccines.
“The research with Ebola actually did lay the foundation for much of what was done with some of the mRNA vaccines that are available today,” Hewlett said in an interview.
Speaking to reporters in January during the HIV Research for Prevention virtual conference, National Institute of Allergy and Infectious Diseases Director Anthony S. Fauci, MD, noted that past research involving a structural biologic approach to HIV vaccines also gave scientists a head start on COVID-19 vaccines.
“HIV research absolutely helped COVID-19. Now that we have a successful vaccine with mRNA, it’s going to go back,” Fauci said. “Everything that goes around comes around. We’re going to hopefully get more insight into HIV vaccines.”
In a blog written in January, NIH Director Francis S. Collins, MD, PhD, said researchers at the NIAID’s Vaccine Research Center “had already been studying coronaviruses for years” when the pandemic struck.
“So, when word came that this was a new coronavirus outbreak, they were ready to take action,” Collins wrote. “It helped that they had paid special attention to the spike proteins on the surface of coronaviruses, which have turned out to be the main focus the COVID-19 vaccines now under development.”
According to experts, the past successes and failures that informed COVID-19 vaccine research were accompanied by a growing knowledge of viruses like SARS-CoV-2, which allowed researchers to better understand what they could potentially be dealing with as the novel coronavirus emerged.
“The fast pace of COVID-19 vaccine development would not have been possible without these previous efforts into understanding the coronavirus, understanding mRNA, understanding nonviral vector vaccines,” Kathryn M. Edwards, MD, an Infectious Diseases Society of America spokesperson and scientific director of the Vanderbilt Vaccine Research Program, told Infectious Disease News.
With all of this previous research available, scientists were able to immediately begin working on vaccines once Chinese scientists shared the novel coronavirus’ genetic sequence last January. Just 2 months after that, on March 16, the NIH announced that it had begun enrolling healthy adult volunteers in the first phase 1 clinical trial evaluating an investigational COVID-19 vaccine, which ended up being mRNA-1273, the vaccine codeveloped by Moderna that received an emergency use authorization from the FDA just 9 months later on Dec. 18.
As of March 30, 2021, there were 84 COVID-19 vaccine candidates in clinical development and 184 in predevelopment, according to tracking by WHO. Almost a third of those vaccine candidates are protein subunit vaccines, the same technology used by Novavax in its COVID-19 vaccine candidate. [Editor’s note: For more on that vaccine, click here.] Eleven are mRNA vaccines, and four are viral vector vaccines.
Fast pace ‘traced to money’
On May 15, 2020, the White House announced the launch of a program called Operation Warp Speed — the government’s multibillion dollar endeavor to accelerate the development, manufacturing and distribution of COVID-19 vaccines, therapeutics and diagnostics. The goal of the initiative, which no longer carries that name, was to produce and deliver 300 million doses of COVID-19 vaccine, with the first doses available by January 2021.
“If you have a commitment on the part of the government in this country and other developed countries to do these things, they get done,” Hewlett said. “One of the reasons why a lot of things become stalled is because the funding for development programs is taken away.”
Hewlett said deep cuts to NIH funding in 2017 affected research projects focusing on coronaviruses.
“That’s the big test and the lesson that should be learned — you don’t wait for a crisis to look at how much funding needs to go into the NIH and other entities, the foundations for research,” he said. “For many, many years, public health departments have been the victims of draconian cuts, there’s no question about it.”
Many of the leading vaccine candidates — included those developed by Pfizer-BioNTech, Moderna, Johnson & Johnson, Novavax and AstraZeneca — received money from Operation Warp Speed.
On Nov. 9, Pfizer and BioNTech released interim phase 3 data showing that their vaccine candidate was more than 90% effective at preventing COVID-19 and showed no serious safety concerns. A week later, Moderna and the NIH also released interim phase 3 data showing that their vaccine candidate had an efficacy rate of nearly 95%, also with no significant safety concerns. In January, Johnson & Johnson released promising data on its one-shot vaccine, reporting that it was 72% efficacious in a U.S. trial.
“I think the fast pace of development can totally be traced to money,” Offit said. “The government put $24 billion in and basically took the risk out for pharmaceutical companies. They paid for phase 3 trials for most of these vaccines. They paid to mass produce these vaccines at their own risk, not knowing whether they were safe or knowing whether they were effective. No company would ever do that.”
In March, the White House announced that Merck would help produce Johnson & Johnson’s COVID-19 vaccine in a federally facilitated partnership between the two competitors that was made possible by the Defense Production Act, with logistical support from the Defense Department. The plan aligned with the Biden administration’s previous vow to address vaccine supply shortages with a “wartime effort.”
Edwards said the pharmaceutical industry deserves credit, too.
“They have done amazing job and companies are making vaccines for other companies,” she said. “Everybody wants the right thing and are willing to work hard and work together, which is so important because this disease is killing so many people and disrupting our way of life.”
Future applications
The vaccines authorized in the U.S. are mostly available only to adults, with the exception of the Pfizer-BioNTech shot, which is available to people aged 16 years or older. However, companies have begun expanding their COVID-19 vaccine research programs to include children, and early results have already been reported. Pfizer and BioNTech said their COVID-19 vaccine was 100% effective in adolescents aged 12 to 15 years, raising hopes that it would be available for that age group by next school year.
There also are indications that COVID-19 vaccine programs are already having an effect on other vaccine research projects. Moderna announced that it was expanding its mRNA vaccine program to develop two vaccines against HIV, three against influenza and one against Nipah virus, which is one of the world’s deadliest pathogens and has made WHO’s list of priority diseases in urgent need of accelerated research.
Moderna said it believes all three can be addressed with mRNA technology. It plans to start phase 1 trials for the HIV and influenza vaccines this year.
“This overall experience is going to impact not only other vaccines and other areas, but it will also have a favorable impact on our ability to respond to changes with the coronavirus,” such as modifying existing vaccines to address the emerging variants, Hewlett said.
Experts have said previously that an Operation Warp Speed-type effort could potentially produce other novel vaccines just as fast.
“Now it has been shown that you can make these vaccines pretty quickly, as we see the advantages of vectored and mRNA vaccines in terms of speed,” Florian Krammer, PhD, a professor of vaccinology at the Icahn School of Medicine at Mount Sinai in New York, told Infectious Disease News.
Krammer said that, in addition to HIV and influenza, the science behind the COVID-19 vaccines could be used to address other infectious diseases such as respiratory syncytial virus. All three have long been top targets of vaccine research.
“I think for future flu pandemics, maybe future pandemics with other viruses, these might be the technologies that we’re going to use first,” Krammer said.
Other experts mentioned influenza vaccine research as a potential beneficiary of COVID-19 vaccine development. Influenza viruses mutate frequently, making it necessary to modify vaccines almost yearly, Hewlett noted. Scientists have long sought to improve influenza vaccines so that people would be protected for more than a year — perhaps even a lifetime. Krammer said a funding effort comparable to what has been spent on COVID-19 vaccine development could probably make a universal flu vaccine a reality in 2 years.
“Since COVID-19 vaccines are so successful, it would suggest that there’s hope for other respiratory diseases,” Edwards said. “The mRNA approach could be used to make influenza vaccines, for example.”
Krammer said one disadvantage of mRNA vaccines is that they need to be stored at freezing temperatures. Further development could make them easier to store, he said.
“We’re about to learn a lot about mRNA vaccines and vectored virus vaccines,” Offit said. “Researchers were looking into those vaccines as ways to prevent HIV, to make a better tuberculosis vaccine, universal flu vaccines, so I think we’re going to learn a lot.”
One specific area in which Offit believes the scientific community will learn from mRNA vaccine development involves pregnant women, who have an elevated COVID-19 mortality rate compared with nonpregnant adult women of childbearing age.
“Normally, when vaccines aren’t tested in pregnant women for approval, the CDC makes them a contraindication for pregnant women — but that didn’t happen here. Pregnant women are actually encouraged to be vaccinated,” he said. “Already, at least 30,000 pregnant women have been vaccinated with these mRNA vaccines, so we’ll learn whether or not there are any problems with the mother or the unborn child as we move forward.”
‘Better prepared now’
Vaccine development is typically conservative, Krammer said.
“It takes ages to go from a new technology to clinical trials, particularly the step from preclinical to clinical. It’s very expensive,” he said.
That was not the case with COVID-19. “Basically unlimited resources” and the understanding that the pandemic could kill millions of people sped up the vaccine development process, Krammer said.
“The resources were there. Everybody realized that this is an absolute priority and everything else was set aside. You don’t have that for regular vaccine development,” Krammer said.
The COVID-19 pandemic also demonstrated that, in addition to adequate funding, vaccine research should involve various technologies, one of which “might turn out to save us from the next pandemic,” Krammer said.
“Today it’s coronavirus; 20 years from now it may be something else,” Hewlett said. “The experience that the scientific community has gained with this particular virus is something that can be easily transferred to another virus, if another new virus comes. We’re certainly much better prepared now than we were before this pandemic started.”
- References:
- CDC. Understanding mRNA COVID-19 vaccines. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html. Accessed March 19, 2021.
- Collins FS. Celebrating the gift of COVID-19 vaccines. NIH Director’s Blog. 2020. Available at: https://directorsblog.nih.gov/tag/barney-graham/. Accessed March 30, 2021.
- Moderna. Moderna’s COVID-19 vaccine candidate meets its primary efficacy endpoint in first interim analysis of the phase 3 COVE study. https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy. Accessed on March 19, 2021.
- Moderna. Moderna COVID-19 vaccine retains neutralizing activity against emerging variants first identified in the U.K. and the Republic of South Africa. https://investors.modernatx.com/news/news-details/2021/Moderna-COVID-19-Vaccine-Retains-Neutralizing-Activity-Against-Emerging-Variants-First-Identified-in-the-U.K.-and-the-Republic-of-South-Africa/default.aspx. Accessed on March 19, 2021.
- Moderna. Moderna provides business update and announces three new development programs in infectious disease vaccines. https://investors.modernatx.com/news-releases/news-release-details/moderna-provides-business-update-and-announces-three-new. Accessed April 1, 2021.
- NIH. NIH clinical trial of investigational vaccine for COVID-19 begins. https://www.niaid.nih.gov/news-events/nih-clinical-trial-investigational-vaccine-covid-19-begins. Accessed on March 19, 2021.
- Pfizer. Pfizer and BioNTech announce vaccine candidate against COVID-19 achieved success in first interim analysis from phase 3 study. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against. Accessed on March 19, 2021.
- Slaoui M, Hepburn M. N Engl J Med. 2020;doi:10.1056/NEJMp2027405.
- U.S. Dept of Defense. Trump Administration announces framework and leadership for ‘Operation Warp Speed.’ https://www.defense.gov/Newsroom/Releases/Release/Article/2310750/trump-administration-announces-framework-and-leadership-for-operation-warp-speed/. Accessed on March 19, 2021.
- WHO. Draft landscape and tracker of COVID-19 candidate vaccines. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. Accessed March 30, 2021.
- Wu K, et al. bioRxvi. 2021;doi:10.1101/2021.01.25.427948.
- Xie X, et al. bioRxiv. 2020;doi:10.1101/2021.01.07.425740.
- For more information:
- Francis S. Collins, MD, PhD, can be reached at mylesr@od.nih.gov.
- Kathryn M. Edwards, MD, can be reached at kathryn.edwards@vumc.org.
- Anthony S. Fauci, MD, can be reached at niaidnews@niaid.nih.gov.
- Dial Hewlett Jr, MD, FIDSA, can be reached at dqhh@westchestergov.com.
- Florian Krammer, PhD, can be reached at florian.krammer@mssm.edu.
- Paul A. Offit, MD, can be reached at offit@chop.edu.
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