If all goes extremely well — with global cooperation, advances and insights to come, overlapping clinical trial phases, and a lot of luck — a year from now a vaccine or even vaccines against the novel coronavirus may exist. But that’s a best-case scenario. Experts tend to be conservative.
“It’s hard for me to see that we’d have a vaccine on this side of January. The process is designed to be slow, reflective, peer-reviewed and evidence-based. It takes a long time, not the science part nor to build the vaccine, but to conduct safety testing in enough people across enough time,” said Gregory A. Poland, MD, director of the Mayo Clinic’s Vaccine Research Group and editor-in-chief of the journal Vaccine.
Can we speed a vaccine?
Development and testing of a vaccine requires greater caution than evaluation of a treatment because a vaccine is given to healthy individuals, Dr. Poland stressed at a webinar for the media organized last week by the Journal of the American Medical Association.
A vaccine typically takes at least 18 months to clear safety and efficacy hurdles. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease (NIAID), dispelled public confusion over FDA approval of a clinical trial versus approval of a product:
Putting a vaccine candidate into a phase 1 clinical trial doesn’t mean you have a vaccine. It will take several months to show safety and then a phase 2 trial to ratchet up the numbers to hundreds or even thousands to test efficacy. That will take 6 to 8 months, so we’re talking about a year to a year and a half to find out if it even works.
A larger phase 3 trial is then needed to fully assess efficacy, providing the numbers and time to recognize adverse effects. “Just because we’ve tested a vaccine in phase 1 and 2 doesn’t mean it is effective. Should we take what you think is a vaccine and give it to people? That’s dangerous. Our first mandate in medicine is to do no harm. There is no vaccine in the immediate future, which tells us we need to rely on public health measures,” Dr. Fauci said.
But because the current need is so compelling, signs of acceleration of the vaccine pipeline have already emerged, Dr. Poland said. Among them:
- Expediting formation of institutional review boards to speed set-up of clinical trials.
- FDA’s shifting reviewers of clinical trial protocols to COVID-19-related proposals.
- Enrolling thousands of people into clinical trials, rather than the typical dozens or hundreds.
Almost unprecedented, Dr. Poland said, is an acceleration to human testing that collapses the normally -in-tandem stages into overlap or parallel. “FDA is allowing non-human primate and human studies to happen simultaneously and move forward more quickly.” The multi-year, multi-phase vaccine development trajectory will contract, like doing all four years of high school in just one.
Lessons learned from SARS vaccines
Novel coronavirus SARS-CoV-2 is still largely an enigma. “While we’ve known about beta human coronaviruses since the 1960s, with this specific strain, nobody’s knowledge is greater than 12 weeks old. We don’t have a lot of pixels on the canvas yet to see the epidemic clearly,” Dr. Poland said.
The best clues we have are from the six-month-long SARS epidemic of 2002/2003.
SARS had a 10% mortality rate, and some people who became reinfected developed severe inflammation.
“Immunity waned quickly against SARS, as well as against four seasonal beta human coronaviruses that cause colds,” Dr. Poland said. If the same is true for the new virus, a vaccine will have to elicit a strong enough immune response to provide the herd immunity essential to protect a population.
We do know how the original SARS virus — SARS-CoV-1 — harmed the human body. It upsets the exquisite balance of the immune response in complex ways. In SARSs, the virus activates the arm that handles parasites and worms (called Th2), while dampening the arm that attacks bacteria and viruses (Th1). (“Th” refers to helper T cells.)
The ensuing chain reaction of immune system mayhem — called a “Th2 immune bias”— is devastating. The body responds with a powerful wash of inflammation, which is a “host response” because it comes from us. At the same time our anti-viral defense fails. Even worse, immune “memory” doesn’t form, which is critical to developing a vaccine.
Examination of bits of lung from people who died from SARS revealed the derangement of the immune response. The off-kilter T cell types triggered a cytokine storm, which is an outpouring of the wrong brew of biochemicals. The cytokine storm precedes the complications that are deadly — acute respiratory distress syndrome, respiratory failure, shock, and organ failure.
We don’t yet know whether the novel coronavirus follows the same “Th2 immune bias” as SARS and MERS, but it’s “probably true,” according to Tanapat Palaga and colleagues from Chulalongkorn University, Bangkok.
Obstacles arose in designing SARS vaccines. In animal studies vaccines triggered the Th2 immune bias. But even worse, the proportion of blood cells called eosinophils skyrocketed. Clinical trials halted after phase 1 when researchers realized that the eosinophil effect might have made people severely sick if they became infected, as had happened with a few other vaccines.
Researchers tried several vaccine approaches against SARS, with no luck:
- Recombinant vaccines against its spike protein, which binds lung cells
- Monoclonal antibodies that grabbed one end of the spikes
- A SARS gene inserted into a flu vaccine and squirted up monkeys’ noses
- A vaccine made in insect cells.
Because all of the potential SARS vaccines caused an outpouring of eosinophils, researchers concluded that the problem lay in the virus, not in the vaccine designs.
But COVID-19 may be more amenable to vaccines than SARS. “The virus isn’t changing genetically that much, and that bodes well for a vaccine,” said Bernhard Wiedermann, MD, a pediatric infectious disease specialist at Children’s National Hospital at a webinar held by the National Organization for Rare Disorders.
Candidate vaccines against the novel coronavirus
Moderna Therapeutics’ “mRNA-1273” is a synthetic snippet corresponding to part of the messenger RNA (mRNA) of the virus that encodes the spike protein. The vaccine programs human cells to manufacture viral peptide antigens (“foreign” molecules that trigger an immune response), and includes a tweak to one type of RNA base that makes the vaccine favor the Th1 attack against viruses.
The company had already been working with the NIAID on the strategy. It has showed promise in animals against MERS, Zika, respiratory syncytial virus, Epstein-Barr, and H7N9 influenza. Other companies have recently joined the mRNA-1273 effort.
Development of mRNA-1273 is rocketing forward. Moderna filed an Investigational New Drug Application with the FDA on February 21 to start a clinical trial, got the OK on March 4, and dosed the first patient on March 16. And all that’s possible because researchers in China published the genome sequence of the novel coronavirus on January 11.
In the trial of mRNA-1273, 45 healthy people ages 18 through 55 will be given the vaccine over a 6-week period, at various centers. With luck, the vaccine will be ready sometime in 2021, said Stéphane Bancel, Moderna’s CEO at a recent online “town hall.” But that “would require 20 different things to work” and “would be a world record,” he added, attributing the speed to the cooperation among the NIH, CDC, FDA, and businesses.
While much vaccine attention is focusing on the spike proteins (S) that festoon the viral surface, other targets are the underlying membrane (M) that shapes mature viral particles; the envelope (E) that oversees the assembly, release, and infectivity of mature viruses; and the nucleocapsid (N) proteins that knit the outer covering.
But would a vaccine focused on one protein type – the spike – inadvertently give an advantage to viral variants that bind to our receptors in different ways, like bacteria resisting overused antibiotics? The possibility of such natural selection concerns Dr. Poland.
“Let’s include S protein and also N and maybe the E or M so that the virus can’t mutate around the vaccine design,” Dr. Poland said. Using more than one viral antigen would coax a more diverse set of antibodies from the immune system, providing broader protection, he added.
A second vaccine candidate, a “synthetic mini-gene” product from the Shenzhen Geno-Immune Medical Institute in China, adopts that multiple-weapon approach.
Their vaccine is called LV-SMENP_DC. Translation: lentivirus (disabled HIV) used to deliver viral proteins (S, M, E, N, and P for polyprotein protease) and also “immune modulatory genes” that activate dendritic cells (DC). The dendritic cells act as “sentries” of the immune response, alerting cytotoxic T cells to attack viruses.
LV-SMENP, which definitely needs a catchier name, is an injection and an intravenous infusion. The 100 enrolled clinical trial participants will be followed for 3 months.
At least LV-SMENP says what it is. Descriptions of a few other vaccine candidates are harder to decipher. CanSino Biologics lists a product at ClinicalTrials.gov consisting of recombinant DNA delivered in an adenovirus. But I can’t tell what, exactly, is the cargo.
Also mysterious is a DNA vaccine called INO-4800, from Inovio Pharmaceuticals. Their claim that a million doses would be available by year’s end — made at the March 2nd meeting of the US Coronavirus Task Force at the White House — may have fueled overoptimism.
“INO-4800 was designed to precisely match the DNA sequence” of the virus, states a company news release. But what part of the viral genome, which is actually RNA, forms the vaccine? Which gene or genes?
The Coalition for Epidemic Preparedness Innovations
A non-governmental organization, the Oslo-based Coalition for Epidemic Preparedness Innovations (CEPI), is attacking COVID-19 on several fronts, which four of the leaders describe in a recent article in The New England Journal of Medicine. Their funding comes from the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the UK).
Some CEPI-supported vaccine candidates:
- The University of Hong Kong’s candidate provides instructions for the spike protein delivered in a weakened influenza vaccine.
- The Institute Pasteure is retooling measles vaccine.
- Novavax is introducing the spike protein in nanoparticles, based on a SARS vaccine that the company “brought out of the freezer.”
While funding organizations like CEPI, governments, academic researchers, and companies will increase efforts to stockpile existing as well as investigational vaccines for known pathogens, they’re also developing “platform technologies to prepare for ‘Disease X’ – a newly emerging epidemic disease, such as Covid-19,” according to CEPI.
Preparedness will also address scalability. How can manufacturing facilities rapidly ramp-up production of millions of vaccine doses? And the Group of Seven has called for a global fair vaccine-allocation program that would use blood tests and other clinical metrics to identify and prioritize the most susceptible populations, should a pandemic recur.
Next time, we’ll be ready.
(Many thanks to Wendy Josephs for sharing her haunted cityscapes.)
Ricki Lewis is the GLP’s senior contributing writer focusing on gene therapy and gene editing. She has a PhD in genetics and is a genetic counselor, science writer and author of The Forever Fix: Gene Therapy and the Boy Who Saved It, the only popular book about gene therapy. BIO. Follow her at her website or Twitter @rickilewis