Cells from African green monkeys. Killed viruses. Spike proteins. People turned into factories.
It takes a lot to teach the human body to fight off disease.
Making a vaccine against the coronavirus that causes COVID-19 involves a variety of technologies and approaches.
There are now more than 150 vaccine development efforts worldwide. Eleven already are being tested in people, and about 50 more are projected to be in clinical trials by the end of the year.
Because it’s unclear which technology will be the best, scientists need to “hedge their bets,” and work on all of them simultaneously, said Dr. Richard Hatchett, CEO of the Coalition for Epidemic Preparedness Innovations, a foundation that finances and coordinates the development of new vaccines.
“We want to have multiple vaccines under development so we can be assured of at least some success,” Hatchett said during a recent webinar sponsored by the American Public Health Association.
With any vaccine, the aim is to get the body’s immune system to recognize a specific pathogen. Once recognized, the immune system develops soldiers poised to attack if that pathogen should appear again during an infection. The hope is these immune soldiers will protect the person from getting sick if exposed, or at least from getting severely ill.
The Chinese government publicly released the genetic sequence of the virus that causes COVID-19, called SARS-CoV-2, in mid-January, just a few weeks after recognizing an outbreak was underway. The move immediately triggered a flurry of vaccine development projects.
Getting the sequence meant developers could begin going after what they knew would be the key target: the so-called spike protein found on the surface of SARS-CoV-2, which gives it its distinctive profile.
They also built on existing technologies wherever possible, using African green monkey cells, for instance, because viruses reproduce efficiently in them and they are well-tested.
One of the challenges now is that scientists still don’t know a lot about what the virus does to the immune system. They are designing a vaccine without knowing how long its benefits will last, for instance, or even what level of immune response they need to generate.
Large clinical trials like one slated to start in July will begin to reveal some of that missing information.
Vaccines often take 15 to 20 years to develop. Researchers are trying now to develop a SARS-CoV-2 vaccine in just a year to 18 months. To meet such a tight deadline, scientists are trying new vaccine technologies under development for years, but have rarely or never been used in large numbers of people.
Those new technologies are exciting to some people, and terrifying to others. That’s why it’s so important, vaccine experts said, to carefully test candidate vaccines.
“We must make sure that in speeding the vaccine development that we do not cut corners in safety and efficacy,” Hatchett said.
Researchers are pursuing a handful of technologies for making a vaccine against SARS-CoV-2. Each has strengths and weaknesses, such as how many shots they will require to provide protection, how hard or expensive they will be to produce at scale, and whether they will need to be kept cold, which would be a challenge to deliver in the developing world.
At a time when the world is desperately waiting for a vaccine, technologies with the longest track record – but that also take the longest to produce – might not be the winning approach. But newer, faster to develop ones still must prove they can be made safe, effective and at a large enough scale to make a difference.
Here are explanations of each of the major technologies, and a few pros and cons, compiled with help from several experts, including Scott Weaver, director of the Institute for Human Infections & Immunity and Scientific Director of the Galveston National Laboratory, in Texas:
Whole virus vaccine: Live-attenuated
Strengths: Live-attenuated whole virus vaccines are the powerhouses of the vaccine arsenal. Used for decades in billions of children, they’ve been safe and effective, for example, in combating measles, mumps and rubella in a combined shot, commonly known as the MMR.
One dose of the MMR vaccine is 93% effective against measles, 78% effective against mumps, and 97% effective against rubella, according to the U.S. Centers for Disease Control and Prevention. A second dose boosts the effectiveness to 97% against measles and 88% against mumps.
These numbers mean roughly 3 out of 100 people can still catch the measles after two injections if there is an outbreak. But people who have been vaccinated will presumably get a lesser infection than if they had not been vaccinated.
Weaknesses: Theoretically, these vaccines also can cause the disease they were designed to prevent. In 2000, the United States discontinued use of an oral polio vaccine that used a live-attenuated virus, because it was capable of occasionally causing the disease.
This approach can also take years to formulate, with researchers struggling to find the right balance – ensuring the virus is weakened enough to be safe, but still powerful enough to trigger an effective immune response.
The mumps vaccine is considered to hold the speed record for vaccine development. It took four years to develop, a time frame that doesn’t make sense in the current pandemic.
Whole virus vaccine: Killed
Strengths: The killed form of whole virus vaccines is considered very effective, as well as safe, because it cannot cause the illness it is designed to protect against. The polio and rabies vaccines, among others, use a killed version of the virus itself to spur the immune system into action.
Weaknesses: In the 1950s, a killed virus vaccine against Respiratory Syncytial Virus, which commonly affects babies and toddlers, made children worse when they caught the virus. The same thing happened in the mid-1960s with a killed measles virus vaccine, said Paul Offit, who directs the Vaccine Education Center at The Children’s Hospital of Philadelphia.
When the RSV and measles viruses, which both have a certain type of protein on their surface, were killed with formaldehyde, it triggered a “weird, aberrant immune response,” he said.
Chinese researchers working on a vaccine against SARS-CoV-2, which has a similar surface protein, have learned this lesson, Offit said. They used something other than formaldehyde to kill the virus used in their candidate vaccine.
Strengths: Protein-based vaccines include ones that prevent shingles, hepatitis B and human papillomavirus. In SARS-CoV-2, a protein-based vaccine would be designed to produce – and get the body to recognize – the spike protein.
These vaccines are relatively easy to manufacture, safe and proven to provide immune responses, said Dr. Larry Schlesinger, CEO and president of Texas Biomedical Research Institute.
Weaknesses: To be effective, this vaccine may need to be paired with an immune stimulant, which can cause side effects, Weaver said. The newer shingles vaccine, for instance, which is a protein-based vaccine, can leave people feeling run-down for a few days.
The other challenge is durability. It’s not clear how long an immune response to SARS-CoV-2 from a protein-based vaccine will last, Schlesinger said.
Viral vector vaccines
Strengths: Viruses are great at invading cells and using their machinery to make more copies of themselves. These vaccines can spur a strong immune response, meaning they’re likely to be effective, Weaver said.
Weaknesses: With the Ebola vaccine, which relies on the vesicular stomatitis virus, people get a mild, flu-like illness and are “not feeling too great for a couple of days,” Weaver said. This means it shouldn’t be used in people who are immunocompromised.
Vaccines based on viruses that cause the common cold, called adenoviruses carry their own risks. They cannot reproduce once they are delivered inside people’s cells, which means that a lot of viral vectors are needed, Offit said. A single dose of one of these vaccines would include 1,000,000,000,000 viral particles, and the idea of giving this vaccine to tens of millions of people makes Offit anxious.
One 2014 study found that people who had received an adenovirus-based candidate vaccine against HIV fared worse than unvaccinated people when infected with HIV.
Also, many people have already been exposed to and built up immunity to adenoviruses. This means the immune system will attack these virus particles before they have a chance to deliver their payload.
That’s why some researchers, including those developing a candidate vaccine at Oxford University, are working with a chimp adenovirus instead. It is believed to be safe, but has not been used before in a vaccine.
Nucleic acid vaccines
Strengths: There’s a lot of excitement in the vaccine development world around a new type of vaccine based on delivering strands of genetic material – essentially an instruction manual to turn people’s cells into spike protein factories.
These vaccines can be developed very quickly. Moderna’s candidate vaccine, called mRNA-1273, was ready to be tested in people just 63 days after the virus’ genetic sequence was made public in January. In part it was able to move so quickly because Moderna was already testing this approach against the flu, chikungunya and Zika.
(While Moderna’s technology is based on RNA, other nucleic acid candidate vaccines use double-stranded DNA, which is more stable. Once inside the person’s cells, this is translated into mRNA and then makes the spike protein.)
Weaknesses: This novel approach to vaccine development has never been tried before in large numbers of people, so there are lots of open questions about its safety and effectiveness.
A second dose probably will be needed for the body to mount an adequate immune response. Frequent boosters could be needed later if immunity is not long-lived, Weaver said.
Also, since nucleic acid vaccines have never been manufactured before at a scale larger than a clinical trial, there is some concern it will be difficult to manufacture enough to make a difference in the global pandemic. But Moderna has said it will be able to make between 500 million and 1 billion doses per year by next year.
No vaccine will be perfect, Schlesinger said. They all have advantages and disadvantages.
But by developing a vaccine, “you can actually really begin to think about eradication” of a disease like COVID-19, he said.
“So, we need those vaccines.”
Contact Weintraub at kweintraub@usatoday.
Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input
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