The idea that old vaccines might have a role in the fight against COVID-19 has been floated since the early days of the pandemic. Vaccines stimulate the broad, innate immune response, which appears to play a key role in fighting COVID-19. Can the approach bridge the time until entire populations are vaccinated specifically against SARS-CoV-2?
Three vaccines dominate the discussion: bacillus Calmette-Guérin (BCG) against tuberculosis; measles, mumps, and rubella (MMR); and oral polio vaccine (OPV).
BCG has been associated with milder courses of infection for respiratory syncytial virus, human papillomavirus, herpes simplex, and influenza. Fifteen clinical trials are testing it for COVID-19, but a drawback is the 1% rate of adverse events.
OPV has also been linked to milder infections for decades. It lowers morbidity from influenza 3.8-fold, and Robert Gallo, MD, of HIV/AIDS fame, .
MMR made headlines in the spring when 955 sailors aboard the U.S.S. Roosevelt tested positive for COVID-19, yet only one was hospitalized. Because recruits routinely receive MMR, re-vaccination of others might prevent the lethal inflammation of COVID-19, according to this and other reports.
Betsy Herold, MD, in the department of microbiology and immunology at Albert Einstein College of Medicine and the department of pediatrics at Montefiore Medical Center, calls the rebirth of MMR vaccine an "intriguing idea," but is skeptical.
"Are kids' vaccinations part of what's revving up their immune systems? No one has data," she said. But the evidence is starting to trickle in.
Vaccines Induce "Trained Innate Immunity"
A virus that gets into the body encounters the complex cascade of defensive proteins that make up innate immunity. That includes cytokines, which are present in "mucosal sites in the lungs, nose, and genitals, and that recruit immune cells. Complement proteins also kill viruses. Because these responses are non-specific, they're called innate," Herold explained.
Cells of innate immunity include macrophages, neutrophils, and natural killer cells, as well as the epithelial and endothelial cells that interface the circulation, said David Hurley, PhD, of the College of Veterinary Medicine at the University of Georgia and part of a team evaluating Merck's MMR II vaccine against COVID-19.
If innate immunity can't contain an infection, the adaptive immune system kicks in: T cells, B cells, and antibodies that bring specificity and memory. Adaptive immunity also hikes cytokine and complement secretion.
Vaccines stand in for a pathogen, triggering powerful "trained innate immunity" that may head off the deadly cytokine storm for which COVID-19 is famous.
Hurley calls a cytokine storm the "turning to the dark side of the innate response." An RNA virus delays interferon (a cytokine) production, blocks signals, and hides from natural killer cells, while replicating explosively until it invades the bloodstream. A wave of inflammation then rages through linings and lymphoid tissues as the adaptive response pours out more cytokines.
"This scenario is not likely to happen if the innate immune system is 'trained' to make interferon early and get ahead of the virus. It will recruit cells to clear the damage so adaptive immunity isn't kicked into overdrive. The virus will be controlled, or at least slowed, and the patient will do better," Hurley said.
Key COVID Innate Immunity Studies
A trio of studies dissects innate immunity in COVID.
AECOM/Montefiore's Betsy Herold and her team compared immune responses in 65 children and youth (under 24) to those of 60 adults, all hospitalized in New York City for COVID-19. They found that an early outpouring of the cytokines interleukin-17A and interferon gamma, released locally into the respiratory tract, may account for the milder cases of most younger people.
"Kids have a strong innate immune system because they don't have pre-existing antibodies and T cells, because they haven't seen the pathogens," Herold told ѻý. Even though children's noses drip nearly constantly this time of year, this isn't a sign of serious illness, she said – just the immune system encountering the world.
"Children have enough of an innate response to SARS-CoV-2 even if viral loads in the nose are high. But they don't get as sick with respect to the respiratory tract, developing pneumonia," Herold said. Innate immunity is even intact in MIS-C (multisystem inflammatory syndrome in children), which reflects a delayed impairment of adaptive immunity.
Qian Zhang, MD, PhD, a research associate at Rockefeller University, and colleagues looked at mutations associated with life-threatening pneumonia from influenza to see if these are overrepresented in COVID-19. The genes encode a type I interferon or receptor. Of 659 people with COVID-19 pneumonia, 23 had a mutation, compared to only one of 534 controls who had mild or asymptomatic COVID-19.
None of the 23 seriously sick patients had ever been hospitalized for viral infections. "Other people who have mutations in these genes have other viral infections, like viral encephalitis. We were super surprised why they could be fine for so many years," yet contract severe COVID, said Zhang. The .
Type I interferon may be helpful as a drug early in the course of COVID, the researchers concluded. ClinicalTrials.gov currently lists more than 100 trials looking into the treatment.
Sagi Shapira, PhD, assistant professor of systems biology at Columbia University Vagelos College of Physicians and Surgeons, was creating an atlas of protein-protein interactions when COVID-19 arrived. When he plugged in SARS-CoV-2 proteins, out popped human complement and coagulation proteins, hallmarks of innate immunity. Such mimicry may illustrate the "escaped gene hypothesis" of viral origin from a host genome.
"If virus mimics complement and coagulation, perhaps people who have clinical histories of complement or coagulation dysfunction have different susceptibility to COVID disease," Shapira said.
His team analyzed health records from 11,116 patients who presented to NewYork-Presbyterian/Columbia University Irving Medical Center with COVID-19 symptoms from February through April. Of the 6,398 who tested positive, 88 had macular degeneration (excess complement), 4 had complement deficiency, and 117 had coagulation dysfunction.
Patients with excess complement or coagulation factors were more likely to be hospitalized or die, independent of other risk factors, according to the findings, .
"The four patients who were SARS-CoV-2 positive and were complement deficient didn't require intubation and didn't die. That highlights how toxic complement can be. Clinical trials are looking at using complement inhibitory drugs," to treat COVID-19, Shapira said.
Putting a Vaccine to the Test: MMR
Clinical trials that investigate repurposing of old vaccines for COVID are starting to yield results.
Hurley's group assessed antibody titers to MMR II components in people recovered from COVID-19, finding "a significant inverse correlation between mumps titers ... and COVID-19 severity," first author Jeffrey E. Gold and colleagues . The innate response would have preceded antibody production.
They compared IgG antibody titers in 30 people who'd had mumps (no vaccine) to 50 people who'd been vaccinated. Among the vaccinated, asymptomatic cases had titers of 134 (in arbitrary units/ml) or higher. Mild cases were below 134, moderate cases below 75, and those who were hospitalized, below 32. The people who'd suffered through the painful swelling of mumps showed no such trend.
The 40-year safety profile of MMR II, well tested on people over 50 and recommended even for those with diabetes, cancer, and autoimmune disease, argues for use against SARS-CoV-2, Hurley said.
"The correlation shown offers a mild risk to a moderate indication of reward -- less severe COVID-19 -- to most healthy individuals," he said. "Until a coronavirus-specific vaccine that provides lasting immunity is available, it seems prudent to seek to prime, arm, and support early innate defense."