Researchers look to messenger RNA encased in nanoparticles, DNA plasmids, molecular clamps and other approaches as they rush to design a vaccine against the new coronavirus.
The Chinese Center for Disease Control and Prevention reported on February 20 that the novel coronavirus illness known as COVID-19 has now infected nearly 75,000 people and that the number of fatalities in China has doubled since February 11, from 1,016 to 2,118. Amid uncertainty about the course of the outbreak, researchers in academia and industry are using a variety of approaches in their urgency to develop a vaccine that will work to contain the virus.
When COVID-19 came on the scene, David Weiner, the director of the Vaccine & Immunotherapy Center at the Wistar Institute in Philadelphia, and his group were already part of a project led by pharmaceutical company Inovio to develop a DNA-based vaccine for Middle East Respiratory Syndrome (MERS), which is caused by a coronavirus. The Coalition for Epidemic Preparedness Innovation (CEPI), whose mission is to accelerate development of vaccines in epidemic situations, funds that project and reached out to Inovio and Weiner to discuss extending the collaboration to vaccine development efforts for the new coronavirus. They agreed and CEPI announced the expanded funding—up to $56 million—on January 23.
“We had been paying very close attention to the [COVID-19] cases increasing over Christmas in China,” Weiner tells The Scientist. As soon as the COVID-19 genetic sequences became available in January, Weiner’s team, and collaborators from Inovio, Université Laval, the National Institutes of Health’s Rocky Mountain Laboratories, and elsewhere, started designing DNA cassettes that encode proteins of SARS-CoV-2, the virus that causes COVID-19.
Their basic approach to vaccine design is to change the nucleotide sequences of these genes to modify the predicted mRNA structures for optimal expression once inside people so that these transcripts abundantly produce the antigens people’s immune systems will recognize. The DNA is injected intramuscularly, then brief electric pulses applied to the site via small needles make the cell membranes more permeable to the genetic material. Then the human cells make viral mRNA and protein from the construct, thereby priming the immune system to fight the virus.
When the group at Wistar and their collaborators went through a similar process for MERS, they chose about 14 different viral proteins and put their corresponding genes together in different combinations that they tested for effectiveness in different cell types. In that case, they went through all the steps, from synthetic DNA to a Phase 1 clinical trial, in about 11 months. The results, published in 2019, showed immune responses to the vaccine, such as the production of neutralizing antibodies and the activation of cytotoxic T lymphocytes, also known as killer T cells. There were no serious adverse events, and a Phase 2 trial is in the works.
In terms of choosing which viral proteins will produce the best immune response, “no one can really be sure what will work, but you tend to want to focus on things that are important for entry,” Weiner says. For instance, the spike proteins that are common to coronaviruses are a good place to start.
“Having the genome sequence allows you to design vaccines for this that are likely to work [based on] what we know about other coronaviruses. The genome sequencing is absolutely crucial,” says Rachel Roper, a biologist at East Carolina University and former program director for the British Columbia Severe Acute Respiratory Syndrome (SARS) Accelerated Vaccine Initiative who is not currently involved in COVID-19 vaccine development.
In the same January 23 announcement, CEPI formalized funding for two other COVID-19 vaccine development projects: an unspecified amount to a collaboration between the National Institute of Allergy and Infectious Diseases (NIAID) and Moderna, a biotech company based in Cambridge, MA, for the development of an mRNA-based vaccine, and up to $10.6 million to the University of Queensland. The Australian team is working on a vaccine composed of synthetic viral proteins with an added stabilization domain called a molecular clamp. The idea is that by holding the synthetic proteins in the conformation that so-called viral fusion proteins maintain before they merge with a host cell, the molecular clamp allows for better recognition of these proteins by the host immune system, leading to greater vaccine efficacy.
On February 18, the Biomedical Advanced Research and Development Authority (BARDA), part of the United States Department of Health and Human Services, and pharmaceutical company Sanofi Pasteur publicized a collaboration to develop their own version of a recombinant protein–based vaccine. Sanofi is already the maker of Flublok, an influenza vaccine built on this approach that is licensed in the US. BARDA will also collaborate with pharmaceutical company Janssen on a project to develop a COVID-19 vaccine.
The need for speed
On January 31, CEPI announced another funding expansion of up to $8.3 million, this time to CureVac, a German pharmaceutical company that also develops mRNA-based vaccines. CureVac was already in the midst of a three-year, $34-million award from CEPI to develop an mRNA printer capable of producing thousands of doses of mRNA vaccine encapsulated in lipid nanoparticles.
“For situations like this one—where you have an outbreak of something that is brand new . . . that was not known to infect humans before—you can then immediately take the code and use the platform that we have to quickly make a vaccine against that virus,” says Lidia Oostvogels, a vice president and area head of infectious diseases at CureVac. “We just need to make messenger RNA, so that is an advantage in an outbreak situation.”
The CureVac team is choosing the viral targets for its mRNA vaccine based on past success. A study the team did in mice for testing a MERS vaccine showed that the technology did induce antibodies against the MERS coronavirus, so they’re starting with what worked then. And to move more quickly, they’re doing things in parallel that they normally would do sequentially. They’ve produced the different candidate vaccines that they’ll test in mice soon, but they are also simultaneously making corresponding candidate vaccines that are of the quality for clinical studies in humans.
“We are making several different candidates because of course we cannot predict exactly which one will be the best,” Oostvogels tells The Scientist. She acknowledges that they will likely end up throwing out some of their options, but acting in parallel will help them to move into Phase 1 clinical trials as early as the beginning of summer. Then, they might have an idea about whether the vaccine induces an immune response by the end of the summer.
It’s not predictable whether the novel coronavirus will spread even further, fade away as SARS did, or perhaps become seasonal like the flu, says Oostvogels. In the case of a seasonal virus, researchers might be able to take more time, on the order of years, to develop a vaccine. It depends “how this disease develops and how this epidemic develops. That will guide how authorities and developers will bring this to the population.”
Oostvogels’s team has shown for other viruses that very low amounts of mRNA packaged in nanoparticles and injected into mice are translated into protein that is able to induce a functional immune response, she adds. “This makes us very hopeful that we would be able to also produce large quantities of the vaccine. If this is a global health threat and you need to vaccinate large parts of the population, you need to have lots of vaccine. It is a lot of work, but it is important and people are dying.”
Another challenge to vaccine development is that the degree of immune response can vary, and it’s not always clear what type of immune reaction will benefit people during infections. Previous work showed that levels of neutralizing antibodies present in MERS patients did not necessarily correlate with the degree of killer T cell responses or outcomes. Because little is known about COVID-19, it’s not clear yet what readouts will best predict vaccine success.
“It’s a great idea to pursue multiple strategies and platforms because we really don’t know what will work best,” Roper says. As such, there are numerous other vaccine endeavors, including testing already existing MERS vaccines to determine their effectiveness for the new coronavirus and a vaccine candidate developed in a collaboration between scientists at NIAID and Oxford University.
A Chinese biotech partners with GSK to boost its coronavirus vaccine development
A Chinese biotech has taken up vaccine maker GSK’s offer to share its vaccine-boosting platform as it works to develop a product that can stop infection from the novel coronavirus, the companies announced Monday.
The company, Clover Biopharmaceuticals, started working on its vaccine last month, as the outbreak of the virus in China grew. Under the partnership, GSK will provide Clover with its proprietary adjuvants — compounds that enhance the effectiveness of vaccines.
“The use of an adjuvant is of particular importance in a pandemic situation since it may reduce the amount of vaccine protein required per dose, allowing more vaccine doses to be produced and therefore contributing to protect more people,” Thomas Breuer, the chief medical officer of GSK Vaccines, said in a statement.
GSK is, as of now, not developing its own vaccine. But the company said earlier this month that it would offer the adjuvant platform to others, in collaboration with the Coalition for Epidemic Preparedness Innovations. Clover is the second program to take advantage of the adjuvants; a CEPI-supported project at the University of Queensland is also trying to develop a vaccine with the adjuvants.
Getting a new vaccine to market requires a large pharma company to get on board; only experienced vaccine makers have the manufacturing capacities needed. But some companies have grown less willing to jump into developing vaccine candidates for each new outbreak after they raced to respond in past emergencies only to wind up empty handed, without a marketed product.
The major vaccine makers have not been as eager as companies working on therapeutics to pivot to the coronavirus, but a number have come around. Last week, Sanofi Pasteur announced it was partnering with a U.S. health agency to make a vaccine using the company’s recombinant DNA platform. Johnson & Johnson’s vaccine division, Janssen, is also at work developing a vaccine.
Smaller biotechs were quick to initiate work on a coronavirus vaccine as the number of cases in China exploded in January, but should their prototypes show promise, they would need a larger partner to manufacture the needed doses for late-stage clinical trials.
Mark Feinberg, president and CEO of the International AIDS Vaccine Initiative and a former Merck scientist, told STAT last week that it is important to have more than one company pursuing a vaccine, given that some could fail in the lengthy development process.
“You don’t ever know what’s going to work and what’s not going to work and it’s not appropriate to put all of your hopes on one single vaccine,” Feinberg said.
Sanofi Announces It Will Work with HHS to Develop Coronavirus Vaccine
The drug maker Sanofi Pasteur is entering the race to develop a vaccine to protect against the new coronavirus sweeping through China, the company announced Monday.
David Loew, Sanofi’s global head of vaccines, announced the company would partner with the U.S. Biomedical Advanced Research and Development Authority—known as BARDA—to make a vaccine using the company’s recombinant DNA platform.
Loew said the company’s previous work to develop a vaccine for SARS—a cousin virus—gives it a leg up on this work.
“Addressing a global health threat such as this newest coronavirus is going to take a collaborative effort, which is why we are working with BARDA to quickly advance a potential vaccine candidate,” said Loew.
“While we are lending our expertise where possible, we believe the collaboration with BARDA may provide the most meaningful results in protecting the public from this latest outbreak,” he said.
Loew said the company expects to have a vaccine candidate—a prototype—to test in vitro within six months and could be ready to test the vaccine in people within a year or 18 months.
Loew noted the DNA recombinant platform is already used to make flu vaccine licensed in the U.S., which means regulators are familiar with it. Sanofi also has large-scale manufacturing capacity for these types of vaccines.
Sanofi is the second major vaccine maker to announce it will try to make a vaccine against the new virus, which has infected over 70,000 people, mostly in China. Johnson & Johnson’s vaccine division, Janssen, has also announced it will try to make a vaccine.