Teachings warn about rushing for first vaccine
People desperate for a coronavirus cure might not want to take the first vaccine that comes along if a better one is likely to come around later.
That is one interpretation of a 60yearold medical doctrine that may be as relevant as ever, given the Trump administration’s push to rush out a vaccine before year’s end.
The Doctrine of Original Antigenic Sin, also known as the Hoskins effect, holds that the antibodies generated by the strain of flu a person first encounters remain in the body for life and affect how the body responds to future infections and vaccinations.
Dr. Jay Levy, a professor of medicine at UCSF, said the doctrine suggests that a person inoculated with a vaccine for COVID19 might develop an
immunological memory to that specific vaccine, which would prevent him or her from benefiting from stronger vaccines produced later.
“The concept is that if you are given, by chance, a less effective vaccine and then later you are given a strong one, your body might not respond to the strong one ... because the immune system thinks it’s getting the same vaccine and it won’t improve the response,” said Levy, a specialist in immunology and virology. “So the message really is, we don’t want to rush into this. We need the vaccine, but we want to make sure we’ve got as good a vaccine as we can make.”
Not all infectious disease specialists agree with that concept — and even if it were so, there are many caveats — but experts say it is something that should be considered in the frantic worldwide race to come out with a drug that will halt the pandemic.
Scientists and medical professionals across the country have expressed concern about President Trump’s recent declarations about the speed with which he expects a COVID19 vaccine to be produced. Most experts do not believe that ambitious timeline provides enough time to complete drug trials, certify that a vaccine is safe and effective, produce millions of doses, transport it around the country, and distribute it to everyone this year.
But an even bigger worry is that important steps might be skipped in order to produce a coronavirus vaccine as quickly as the president wants, and that could lead to a flawed product. If, in that case, Levy’s interpretation of the Doctrine of Original Antigenic Sin holds true, it would mean millions of people could be inoculated with an inferior vaccine and be stuck with the consequences.
Robert Siegel, an infectious disease specialist at Stanford University, said the doctrine is a fascinating concept, but it doesn’t address coronaviruses and is more nuanced than just saying people bedeviled by the pandemic are stuck with taking only one vaccine.
“I am far more concerned about the release of an inadequately tested vaccine that is not safe and/ or efficacious,” Siegel said. “I am also concerned that a prematurely released vaccine could hinder the ability to do proper testing on that vaccine or on other potential vaccine candidates.”
The original paper on the Doctrine of Original Antigenic Sin was published by Dr. Thomas Francis in the Dec. 15, 1960, edition of the Proceedings of the American Philosophical Society.
The concept, first named by Francis in the 1950s and later dubbed “first flu is forever,” described how the imprint made by that first virus “governs antibody response to vaccinations with other strains.” The paper said antibodies from that first strain are amplified, or bolstered, by every subsequent exposure to the flu.
In a nutshell, it means that doctors can test people’s blood and determine which strain of influenza was around when they were kids. It also suggests that booster shots for that strain can provide useful protection against other similar strains.
If, however, a new strain of flu different from the original is encountered later in life, the cellular memory established in that first infection would tend to delay or dampen the effectiveness of the immune response, according to the doctrine.
A 2017 paper published in the Journal of Infectious Diseases cited studies in the United States and Canada that indicated “that prior influenza vaccination can, in certain situations, produce actual increased susceptibility to infection.”
Siegel said this phenomenon has been seen in the mosquitoborne tropical virus called Dengue fever, which has four serotypes, or strains, or five if you count the Zika virus.
“In this case, a secondary infection with a different strain not only interferes with the proper immune response, it actually causes the response to go haywire and make the clinical disease worse than if the person had never been exposed to Dengue,” said Siegel, describing what he called “antibody dependent enhancement.”
The antigenic sin concept is still being debated six decades after Francis came up with it. The 2017 paper said “the doctrine is still invoked to explain observations that may but often may not relate to its original description, such as reductions in the response to antigens” in flu vaccines.
And it is an open question whether the doctrine applies to SARSCoV2, the specific coronavirus that causes COVID19, Siegel said. For all anybody knows, he said, taking two different vaccines might result in cross protection against different strains, which would be a good thing.
The first vaccine for shingles, a painful skin infection caused by the same virus that causes chicken pox, was later improved upon and no adverse effects were reported in people who took both versions.
But the possibility does exist that an inadequately tested coronavirus vaccine could interact with a different strain still circulating in the population and hinder the body’s ability to make strong neutralizing antibodies. That could potentially leave people unprotected or even enhance disease, Siegel said.
“In theory, this could happen if there were two vaccines aimed at the same protein from two different strains of the virus,” Siegel said. But “in a properly tested vaccine, this eventuality would be detected before the vaccine was licensed.”
Bad outcomes like that may be unlikely, he said, but “we need to get the actual data to determine which of these possibilities is correct.”
The race for a cure in the United States is largely being driven by Operation Warp Speed, designed by the Trump administration to cut bureaucratic red tape and speed the approval process.
The pharmaceutical firms leading the race — Pfizer, Moderna, AstraZeneca and Johnson & Johnson — have vowed not to seek government approval for any vaccine that hasn’t proven to be safe and effective. That means testing it on people of different ages, genders and ethnicities and on different strains and lineages of the virus to see if there are side effects, a process most believe won’t be complete until at least the spring.
Original antigenic sin may or may not come into play, Siegel and Levy said, but the mere possibility is reason enough not to bypass science and rush an unproven coronavirus vaccine into use.