[...]

De Groot began developing her algorithms while teaching at Tufts University in 1994. While she has landed several small grants for EpiVax since it began, a breakthrough occurred last winter when EpiVax received a $900,000 grant from the Sequella Global TB Foundation in Rockville, Md. De Groot was one of 11 core researchers selected by Sequella, which was using money from the Gates Foundation.

"She's very forwad-thinking," said Carol Macy, Sequella president, of De Groot.  "Her approach has been undrestimated for the last five years. But people recognize she has a tool ... to leapfrog over many mistakes In the past and get to the meat of the problem."

To finance the research, EpiVax contracts with companies using her algorithms to analyze information. The vaccine division of American Home Products in New York has been a client, as has the biotech company Genentech in California.

De Groot is also constantly applying for grants; during the first six months of this year she applied for five. She's waiting to hear if EpiVax will be awarded half of a $3.9 million grant she applied for with another researcher from Britain.

Recently EpiVax and the TB/HIV Research Lab at Brown, which De Groot directs, announced the formation of a nonprofit partnership to make an AIDS vaccine available at ''little or no cost'' to recipients. The researchers from both groups say they hope to have an HIV vaccine in clinical trials within five years.

PROVIDENCE – The equipment and building are new, but there is something familiar about Annie De Groot’s new digs: her father, who was among her first faculty appointments at the University of Rhode Island.

When Annie De Groot, a Brown University professor and the chief executive officer of EpiVax, was given the job of directing the new Immunology and Informatics Institute at URI, she was quick to recruit her dad, Leslie J. De Groot.

“He has a 400-pound CV,” referring to his Curriculum Vitae, or resumé, she said, “and international recognition.”

The De Groots have crossed professional paths before. De Groot, 80, served for three decades on the faculty of the University of Chicago, where his daughter attended medical school. But they never studied together.

“When you’re that age,” she said, “you don’t want to hang out with your dad.”

They have published together, but the two did not share an office until January 2005, when Annie De Groot, 53, convinced her father to move to the East Coast, where he owns a vacation home in Nonquitt, Mass., and a sailboat moored at Padanaram Harbor.

Brown offered Leslie De Groot a position in the endocrine division and space in his daughter’s lab.

It did not take much negotiation, Annie De Groot said, given her father’s publication record and the National Institutes of Health grant that pays his salary and provides research support.

For most of Annie De Groot’s career, her research had led her far from her father’s
medical practice. Before starting the HIV and tuberculosis program at Brown in 1992, for example, she traveled several times to Africa.

She and her father never saw eye-to-eye on political questions. But in many ways, she modeled her career on his, continuing to see patients even as her research took off. “To me, that’s just what doctors do,” she said.

Over the years, Annie De Groot said, she increasingly saw similarities in their research topics. “We’d go to family reunions and always end up in a corner talking about science,” De Groot said. “Our interests overlap.”

Recently, Leslie De Groot moved his equipment to the new URI lab, where he is studying the thyroid disorder Graves disease. The two have applied for their first father-daughter grant. “He’s not going to live forever. I figured, here’s something we both enjoy, let’s do it in the same space.”

Dr. Anne S. De Groot went to medical school, she said, “to right the wrongs that had been wrought” in women’s health care. She planned to work in obstetrics and gynecology, but was angered by the attitudes of many men in her specialty. Then, in Africa, she found a new calling.

It was her last year at the Pritzker School of Medicine at the University of Chicago, and she did a rotation in a mission hospital in Zaire. She traveled with missionaries and worked on a measles campaign, then spent time in South Africa, treating patients with township nurses.

She saw firsthand the toll of infectious diseases and was struck by how fighting them put doctors at the intersection between social injustice and personal choices. Vaccines, she realized, are “a scientific intervention that has a social impact” – a powerful way for her to make a difference in the world.

For most of the last 25 years, that has been De Groot’s focus. After completing her residency in internal medicine at Tufts New England Medical Center, she took a National Institutes of Health Fellowship in immunoinformatics and vaccine research, then returned to Tufts for specialized clinical training in infectious diseases.

She focused on two diseases in particular: tuberculosis, which had made a comeback in the United States in the late 1980s, afflicting many homeless people in the cities, and AIDS, for which there were few effective treatments at the time.

In 1992, armed with an NIH grant to help her launch her research career, she joined the Brown University medical faculty and opened the TB/HIV Research Laboratory. Within years, she had developed sophisticated software to map epitopes, the surfaces on molecules that can elicit an immune response – and are thus essential to vaccine development.

She called the technology EpiMatrix. In 1998, she and her research partner Bill Martin founded EpiVax Inc. and licensed the algorithms, using them in-house to develop vaccines for HIV, tuberculosis, smallpox and others, and making them available to industry clients.

It was cutting-edge work, drawing national and international attention – and major grants – to De Groot’s lab well before Rhode Island set out to become a biotechnology hub.

De Groot, Martin and their team took on a wide range of projects, mostly involving vaccines but also therapies that needed to be altered to avoid triggering an immune response. And they continued to upgrade and expand their technology, even breeding a new kind of lab mice that had been genetically altered to more closely mimic the human immune system.

But much as EpiVax is a business, De Groot has always wanted her work to benefit even those who could never afford to pay for medications. So in 2001, she co-founded the Global Alliance to Immunize Against AIDS (GAIA) Vaccine Foundation, a nonprofit that aims to develop a global HIV vaccine available to all who need it, and while the vaccine is under development, to lay the groundwork that will be needed to conduct clinical trials in sub-Saharan Africa.

De Groot also remained active in academia, continuing her research at Brown, teaching vaccinology to a new generation of scientists and mentoring young women.

Through that work, said Betsy Stubblefield Loucks, a former student and current EpiVax collaborations manager, “Dr. De Groot has helped launch countless young women into careers in public health, medicine, biotechnology, life science and social justice.”

De Groot hired her two weeks after she graduated from Brown, Loucks noted, and for two and a half years, she learned, grew and expanded her horizons by working on HIV/AIDS advocacy with De Groot. “She taught me to be fearless,” Loucks wrote in nominating De Groot for the 2009 Business Women Career Achievement award, “to question the status quo, and [to] never underestimate the power one individual has to change the world.”

De Groot has also treated patients for all these years, but not just anyone. Mentors in Chicago and at Tufts got her involved in treating TB, and in Rhode Island, she has worked with TB patients at the state clinic run by Roger Williams Medical Center and through The Miriam Hospital. And after working in the AIDS ward in the early 1990s at Boston’s Lemuel Shattuck Hospital, a public facility that treated the poor and uninsured, she treated HIV-infected women in prisons for more than 12 years.

“There are few more creative, energetic, brilliant forces in science than people like Annie,” raved Jeffrey R. Seemann, outgoing dean of the University of Rhode Island’s College of the Environment and Life Sciences and co-chair of the R.I. Science and Technology Advisory

Council, who recently recruited De Groot to lead a new Institute for Immunology and Informatics at URI’s Providence Campus. Seemann plans to leave URI to become vice president of research at Texas A&M University on July 1.

Providence Mayor David N. Cicilline, who has been working with De Groot – and Seemann – to develop a biotech research hub in the Jewelry District, called De Groot “an incredibly talented scientist and researcher” of national renown and “a leading entrepreneur in our emerging biotech economy.”

Looking ahead, De Groot has many goals: a successful HIV vaccine, of course, and successful new drugs developed at EpiVax. But she also wants to work with other biotech companies to put EpiVax tools to work in advancing their own projects, and she wants to train a new generation of scientists to use these technologies in even more ways.

“What I’d like to do is to build a world-class institute for training young people … that the immunoinformatics community has built, to design better drugs and vaccines,” she said. EpiVax’s toolscan be used in far more ways than the company can manage on its own, she added, “so we need to have more people working with the tools to do projects we won’t have time to do.” •

 PROVIDENCE – Five Rhode Island-based nonprofits will receive 2017 Best Practice awards from the Rhode Island Foundation Tuesday, according to a Monday statement by the organization.

Clinica Esperanza, Day One, Foster Forward, Hattie Ide Chaffee Home and Trinity Repertory Co. – the five nonprofits that will be honored Tuesday – “emerged from a highly competitive process and an impressive group of nominees,” Jill Pfitzenmayer, vice president of the foundation’s Initiative for Nonprofit Excellence, said in prepared remarks. “There is something in each of their remarkable achievements that can help any nonprofit become even more effective.”

Sponsored by Blue Cross & Blue Shield of Rhode Island, the awards recognize collaboration, communications, innovation, leadership and volunteer engagement. They are as follows:

• The Volunteer Engagement Award will be presented to Providence’s Clinica Esperanza for its more than 7,000 hours of volunteer service following recruitment of physicians, nurses, nurse practitioners, medical students, pharmacy students and others to help the outfit, which provides health care to uninsured adults.

• Day One, also out of Providence, will be awarded the Collaboration Award for its implementation of the Uniform Response Protocol, which improves how the state addresses the commercial sexual exploitation of children.

• The Innovation Award will be given to East Providence’s Foster Forward in recognition of its Works Wonders program – a comprehensive, trauma-informed career-readiness program for youth who have aged out of foster care.

• Cutting hospital emergency room admission rates by 60 percent for clients discharged after short-term stays, East Providence’s Hattie Ide Chaffee Home will be presented the Communications Award.

• Highlighting the short-term and long-term financial moves set in motion by the Trinity Repertory Co., which were designed to maximize stakeholder buy-in and address critical financial and strategic issues facing the theater, the Providence theater will receive the Leadership Award.

Each award recipient will be given a $1,000 grant, a promotional video highlighting their work as well as tuition waivers to any Rhode Island Foundation INE professional-development workshop or seminar taking place in the next year.

The awards ceremony will take place at 5:30 p.m. at the BCBSRI Providence headquarters at 500 Exchange St.

In 2016, the foundation awarded a record $45 million in grants to organizations addressing the state’s most pressing issues and needs of diverse communities.

Only 6 months after the first identification of the causative coronavirus, vaccine candidates against COVID-19 are already in clinical trials. The secret weapon behind the speed of development? Computational immunology.

When Chinese officials posted the sequence of the coronavirus SARS-CoV-2 on 10 January 2020, it triggered a race among vaccine manufacturers. Historically, this process has taken years, even decades. The vaccine against the Ebola virus, which zoomed through human trials in a record-breaking 5 years, took more than twice as long in preclinical development. However, SARS-CoV-2 was different. Within a few hours, several companies had developed potential vaccine targets.

Understanding the immune system is a tall order, says Maggie Ackerman, an immunologist at Dartmouth College, in Hanover, New Hampshire. It is why so many scientists like her have turned to computational and informatics approaches, mathematical models that have become so sophisticated they can predict which parts of a novel pathogen will be recognized by B cells and T cells or create targeted immunotherapies against tumor cells.

When the novel coronavirus struck, years of work on these models meant that scientists were poised to respond immediately. By being able to predict the exact parts of SARS-CoV-2 that would elicit an immune response, scientists have been able to sprint through the early stages of vaccine development and into animal trials.

“These approaches offer incredible speed at getting from genetic sequence to a candidate vaccine. Nothing can compete with that,” says Ackermann.

It all started with a copy–paste

One of the main reasons scientists first turned to computational tools to understand the immune system is that they needed to. Millions of years of natural selection have meant that the immune system has created multiple layers of defense with the redundancy and adaptability to meet nearly any threat it is faced with. The end result is an organ system that, even today, researchers still do not fully understand.

Because most of the early work in immunology was in mice, there is detailed understanding of the mouse immune system, explains Mark Davis, a computational immunologist at Stanford University, in California. However, understanding what is going on in humans is another story.

“Mathematical models, statistical approaches, and machine learning are the only way you can make meaning out of so much data,” says Maia Smith, a bioinformatics engineer at AbCellera in Vancouver, Canada.

As the field of bioinformatics grew, immunologists began borrowing some techniques used by geneticists and systems biologists, which ultimately created the subfield of computational or systems immunology.

These mathematical models started off with relatively simple ordinary and partial differential equations that let scientists describe and predict how a system changes over time and space, says Filippo Castiglione, a computational immunologist at the Institute for Computing Applications at the National Research Council of Italy.

The mid-1990s were a turning point for the field of immunology. At the time, the escalating human immunodeficiency virus (HIV)–AIDS crisis and early DNA sequencing results from the Human Genome Project had begun to generate large datasets on immune functioning. This gave immunologists a newfound urgency for addressing the deadly pandemic, as well as a starting point for developing their models, according to Annie De Groot, chief executive officer and founder of the computational immunology company EpiVax in Providence, Rhode Island.

The problem was that when immunologist started in this field, it was very difficult to get funded, because people just did not believe that computers could do this, De Groot says.

To be fair, compared with the sophistication of current tools, De Groot’s initial computational algorithms were rather simple. At the time, she was a postdoc in the lab of [Dr. Jay Arthur Berzofsky (born 1946)] and was working to understand how T cells recognize pathogens. As soon as Helicobacter pylori was first sequenced, in 1997, she simply copied and pasted the sequence into a word processor and ran some macro, looking to identify peptides recognized by major histocompatibility complex (MHC) class II proteins ― and it worked.

De Groot continued to search the literature for more peptides and MHC class II proteins to be able to improve the precision of her computations as she started her own lab working on tuberculosis and HIV at Brown University. What resulted was EpiMatrix, a computer algorithm that breaks down a pathogen’s protein sequences into chunks that are ten amino acids in length, and then ranks them by their likelihood of binding to a given MHC protein. The output is an estimated binding probability that compares the algorithm’s predictions with its score of known MHC binders and non-binders.

When De Groot tested the program in Mycobacterium tuberculosis to identify proteins that might make good vaccine candidates, she was able to reduce the number of epitopes by 99.8%, from 1.6 million to 3,000. The algorithm also identified conserved HIV epitopes that are recognized by MHC proteins.

Making sense of all the data

As De Groot toiled away to find MHC class II epitopes, other researchers were using differential equations to identify a target for a universal vaccine against influenza, a task that became more urgent with the 2009 H1N1 influenza pandemic. Both HIV and the influenza virus mutate at staggering rates, which means that vaccinologists had to try to find epitopes that remain constant over time and elicit a strong and durable immune response. It was a tall order, since those epitopes most recognized by the immune system were also the most variable.

However, scientists at Oxford University created a set of equations to model the evolution of seasonal influenza virus from year to year and found that they could identify epitopes that would fit both those criteria, which made them good candidates for a universal vaccine against influenza. Equations predicted that these epitopes would wax and wane over time as populations developed immunity, something the researchers verified in human samples in a 2018 paper in Nature Communications. A US-based startup, Blue Water Vaccines, licensed this strategy and is using it to develop a universal vaccine against influenza.

Justin Bahl, an epidemiologist at the University of Georgia, in Athens, Georgia, also took clues from evolutionary biology to try and trace the evolution of influenza virus strains and see if he could identify a common ancestor that might be useful in vaccine design. Rather than modeling the future evolution of the genetic code of influenza virus, Bahl instead tried to predict what the virus’s RNA sequences and protein structures looked like in the past.

“If we know what’s conserved in all of these different influenza viruses, we can combine that with what’s conserved in the human body response,” Bahl says.

What these volumes of data perhaps illustrated best was the heterogeneity of immune responses. The vaccine against hepatitis B virus is often given at birth, and while some people need only one dose to be fully protected, others need two or three, says Richard Scheuermann of the J. Craig Venter Institute in San Diego, California. He and his colleagues studied immune cells from samples collected before and after vaccination and used single-cell RNA sequencing followed by machine learning to identify what contributes to different vaccine responses. Computational methods, Scheuermann says, helped them narrow down a number of candidate genes expressed specifically by dendritic cells. “We ended up with only a dozen genes to evaluate, which is a much more specific signal,” he says.

The answer, Scheurmann’s team found, was the number of myeloid dendritic cells expressing a gene called NDRG2, according to a 2018 study in the Journal of Immunology. With these results, Scheuermann says, he can investigate whether adjuvants designed to boost the immune response to a vaccine will affect the activity of NDRG2 in myeloid dendritic cells.

Instead of relying on mathematical models based on differential equations, Castiglione and other scientists have begun using agent-based models. These models treat each cell or other entity as an agent that is defined by a set of rules that also incorporate some randomness, with the goal of determining their effects on the system as a whole. The result is a distribution of probabilities for a variety of outcomes, instead of an estimate of average behavior. Combining this with neural networks and other machine-learning techniques has allowed Castiglione to predict the existence of a phenomenon called ‘memory anti-naive’, in which cross-reactive memory T cells inadvertently inhibit the formation of a more effective T cell response to a secondary infection.

Computational immunology can fast-forward the research, but is not a shortcut

These computational approaches are especially good at generating hypotheses, according to bioinformatician Sagi Shapira of Columbia University, in New York, New York. He points to work by Peter Howley of Harvard University, in Cambridge, Massachusetts, who asked why certain strains of human papillomavirus are associated with cervical cancer and others are not. Bioinformatics data showed that equivalent proteins in different human papillomavirus strains bind to a different constellation of host proteins in the cell. Howley hypothesized that these differences could explain why some strains cause cancer. It allowed Howley and other immunologists to hone their hypotheses more finely before diving into expensive and time-consuming ‘wet lab work’.

When it comes to designing vaccines and antibody therapies, building a viable candidate can take years and cost tens of millions of dollars. By developing and investing in the advanced computational tools used by scientists at EpiVax, Moderna, AbCellera and other companies, this process can be compressed into hours instead of years. Although De Groot’s databases and mathematical modeling have grown exponentially more sophisticated, compared with her original Microsoft Word–based endeavors, she still keeps the recognition of peptides by MHC class II proteins at the center of her analysis. However, she also looks for sequences that may alert regulatory T cells and dial back the immune response, as well as modeling how the use of two different peptides might affect immunogenicity. At AbCellera, scientists have whittled down the billions of antibodies found in a sample of blood from someone who has recovered from COVID-19 to a top few candidate antibodies from which an effective blocking epitope could be identified. The key to this process has been the start-up’s immunoinformatics tools that can link antibody to antigen. Developing their antibody therapy even further will occur in collaboration with Eli Lilly.

Shapira also cautions that no in silico analysis, no matter how high-quality the input and how exacting the computational algorithms, will ever be a substitute for experimental data. Many hypotheses and many vaccines against malaria and HIV, and even universal vaccines against influenza, have looked good on paper but been a flop when tested in humans. There is also the ongoing issue of reproducibility, an issue that has plagued much of science but has hit many ‘-omics’ studies especially hard.

“There’s no shortcut to actually doing the experiment,” Shapira says.

The testing stage is where both EpiVax and AbCellera are at with their COVID-19 response. AbCellera began phase 1 human trials of a SARS-CoV-2-neutralizing monoclonal antibody called ‘LY-CoV555’ that targets the virus’s spike protein. Also, EpiVax is collaborating with several labs to develop candidate vaccines, some of which have already begun preclinical studies. Moreover, AbCellera has teamed up with Eli Lilly to identify the best antibodies from the blood of patients who have recovered from SARS-CoV-2 infection to create a monoclonal antibody therapeutic. To De Groot, more than two decades of work in computational immunology was what enabled her company to be able to develop a vaccine candidate in just a few hours.

“With the tools that we have, we can pivot to whatever seems to be capturing public interest at the moment,” De Groot says, “and eventually we can address those really big problems.”

doi: https://doi.org/10.1038/d41591-020-00027-9

Seven months into the coronavirus crisis, with more than 30 vaccines rapidly advancing through the rigorous stages of clinical trials, a surprising number of research groups are placing bets on some that have not yet been given to a single person.

The New York Times has confirmed that at least 88 candidates are under active preclinical investigation in laboratories across the world, with 67 of them slated to begin clinical trials before the end of 2021.

Those trials may begin after millions of people have already received the first wave of vaccines. It will take months to see if any of them are safe and effective. Nevertheless, the scientists developing them say their designs may be able to prompt more powerful immune responses, or be much cheaper to produce, or both — making them the slow and steady winners of the race against the coronavirus.

“The first vaccines may not be the most effective,” said Ted Ross, the director of the Center for Vaccines and Immunology at the University of Georgia, who is working on an experimental vaccine he hopes to put into clinical trials in 2021.

Many of the vaccines at the front of the pack today try to teach the body the same basic lesson. They deliver a protein that covers the surface of the coronavirus, called spike, which appears to prompt the immune system to make antibodies to fight it off.

But some researchers worry that we may be pinning too many hopes on a strategy that has not been proved to work. “It would be a shame to put all our eggs in the same basket,” said [Dr. David J. Veesler (born 1981)], a virologist at the University of Washington.

In March, Dr. Veesler and his colleagues designed a vaccine that consists of millions of nanoparticles, each one studded with 60 copies of the tip of the spike protein, rather than the entire thing. The researchers thought these bundles of tips might pack a stronger immunological punch.

When the researchers injected these nanoparticles into mice, the animals responded with a flood of antibodies to the coronavirus — much more than produced by a vaccine containing the entire spike. When the scientists exposed vaccinated mice to the coronavirus, they found that it completely protected them from infection.

The researchers shared their initial results this month in a paper that has yet to be published in a scientific journal. Icosavax, a start-up company co-founded by [Dr. David J. Veesler (born 1981)]'s collaborator, Neil King, is preparing to begin clinical trials of the nanoparticle vaccine by the end of this year.

U.S. Army researchers at the Walter Reed Army Institute have created another spike-tip nanoparticle vaccine, and are recruiting volunteers for a clinical trial that they also plan to start by the end of 2020. A number of other companies and universities are creating spike-tip-based vaccines as well, using recipes of their own.

Immune punch

Antibodies are only one weapon in the immune arsenal. Blood cells known as T cells can fight infections by attacking other cells that have been infiltrated by the virus.

“We still don’t know which kind of immune response will be important for protection,” said Luciana Leite, a vaccine researcher at Instituto Butantan in São Paulo, Brazil.

It’s possible that vaccines that arouse only antibody responses will fail in the long run. Dr. Leite and other researchers are testing vaccines made of several parts of the coronavirus to see if they can coax T cells to fight it off.

“It’s a second line of defense that might work better than antibodies,” said [Dr. Anne Searls De Groot (born 1956)], the C.E.O. of [EpiVax], a company based in Providence, R.I.

Epivax has created an experimental vaccine with several pieces of the spike protein, as well as other viral proteins, which it plans to test in a clinical trial in December.

The effectiveness of a vaccine can also be influenced by how it gets into our body. All of the first-wave vaccines now in clinical trials have to be injected into muscle. A nasal spray vaccine — similar to FluMist for influenza — might work better, since the coronavirus invades our bodies through the airway.

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Several groups are gearing up for clinical trials of nasal spray vaccines. One of the most imaginative approaches comes from a New York company called Codagenix. They are testing a vaccine that contains a synthetic version of the coronavirus that they made from scratch.

The Codagenix vaccine is a new twist on an old formula. For decades, vaccine makers have created vaccines for diseases such as chickenpox and yellow fever from live but weakened viruses. Traditionally, scientists have weakened the viruses by growing them in cells of chickens or some other animal. The viruses adapt to their new host, and in the process they become ill-suited for growing in the human body.

The viruses still slip into cells, but they replicate at a glacial pace. As a result, they can’t make us sick. But a small dose of these weakened viruses can deliver a powerful jolt to the immune system.

Yet there are relatively few live weakened viruses, because making them is a struggle. “It’s really trial-and-error based,” said J. Robert Coleman, the chief executive of Codagenix. “You can never say exactly what the mutations are doing.”

The Codagenix scientists came up with a different approach. They sat down at a computer and edited the coronavirus’s genome, creating 283 mutations. They then created a piece of DNA containing their new genome and put it in monkey cells. The cells then made their rewritten viruses. In experiments on hamsters, the researchers found that their vaccine didn’t make the animals sick — but did protect them against the coronavirus.

Codagenix is preparing to open a Phase 1 trial of an intranasal spray with one of these synthesized coronaviruses as early as September. Two similar vaccines are in earlier stages of development.

The French vaccine maker Valneva plans to start clinical trials in November on a far less futuristic design. “We are addressing the pandemic with a rather conventional approach,” said Thomas Lingelbach, the C.E.O. of Valneva.

Valneva makes vaccines from inactivated viruses that are killed with chemicals. Jonas Salk and other early vaccine makers found this recipe to work well. Chinese vaccine makers already have three such coronavirus vaccines in Phase 3 trials, but Dr. Lingelbach still sees an opportunity for Valneva making its own. Inactivated virus vaccines have to meet very high standards for purification, to make sure all the viruses are not viable. Valneva has already met those standards, and it’s not clear if Chinese vaccines would.

The United Kingdom has arranged to purchase 60 million doses of Valneva’s vaccine, and the company is scaling up to make 200 million doses a year.

Faster and cheaper production

Even if the first wave of vaccines work, many researchers worry that it won’t be possible to make enough of them fast enough to tackle the global need.

“It’s a numbers game — we need a lot of doses,” said Florian Krammer, a virologist at Icahn School of Medicine at Mount Sinai in New York City.

Some of the most promising first-wave products, such as RNA vaccines from Moderna and Pfizer, are based on designs that have never been put into large-scale production before. “The manufacturing math just doesn’t add up,” said Steffen Mueller, the chief scientific officer of Codagenix.

Many of the second-wave vaccines wouldn’t require a large scale-up of experimental manufacturing. Instead, they could piggyback on standard methods that have been used for years to make safe and effective vaccines.

Codagenix, for example, has entered into a partnership with the Serum Institute of India to grow their recoded coronaviruses. The institute already makes billions of doses of live weakened virus vaccines for measles, rotaviruses and influenza, growing them in large tanks of cells.

Tapping into well-established methods could also cut down the cost of a coronavirus vaccine, which will make it easier to get it distributed to less wealthy countries.

Researchers at Baylor College of Medicine, for example, are doing preclinical work on a vaccine that they said might cost as little as $2 a dose. By contrast, Pfizer is charging $19 a dose in a deal with the U.S. government, and other companies have floated even higher prices.

To make the vaccine, the Baylor team engineered yeast to make coronavirus spike tips. It’s precisely the same method that has been used since the 1980s to make vaccines for hepatitis B. The Indian vaccine maker Biological E has licensed Baylor’s vaccine and is planning Phase 1 trials that will start this fall.

“They now already know they can make a billion doses a year,” said Maria Elena Bottazzi, a Baylor virologist. “It’s easy-breezy for them, because it was exactly the same bread-and-butter vaccine technology that they have been working with for years.”

Even if the world gets cheap, effective vaccines against Covid-19, that doesn’t mean all of our pandemic worries are over. With an abundance of other coronaviruses lurking in wild animals, another Covid-like pandemic may be not far off. Several companies — including Anhui Zhifei in China, Osivax in France and VBI in Massachusetts — are developing “universal” coronavirus vaccines that might protect people from an array of the viruses, even those that haven’t colonized our species yet.

Many scientists see their ongoing vaccine work as part of a long game — one that the well-being of entire nations will depend on. Thailand, for example, is preparing to purchase Covid-19 vaccines developed overseas, but scientists there are also carrying out preclinical research of their own.

At Chulalongkorn University, researchers have been investigating several potential candidates, including an RNA-based vaccine that will go into Phase 1 studies by early 2021. The vaccine is similar to one that Pfizer is now testing in late-stage clinical trials, but these scientists want the security of making their own version.

“While Thailand has to plan for buying vaccines, we should do our best to produce our own vaccine as well,” said Kiat Ruxrungtham, a professor at Chulalongkorn University. “If we are not successful this time, we will be capable to do much, much better in the next pandemic.”