Urgent Need for ‘Universal’ Vaccines for SARS-CoV-2
‘If we may need it, we better be working on it’
There is an emerging general consensus in the scientific community that is two-fold: COVID-19 is not going away anytime soon, and continuous vaccine boosters eventually could yield diminishing returns.
What is needed are new, second-generation vaccines that confer broader immunity against both circulating variants and mutations yet to arise, says Dan Lucey, MD, MPH, a pandemic expert and member of the Infectious Diseases Society of America (IDSA).
Suggesting the pandemic response has been more reactionary that proactive, Lucey said there should be a sense of urgency about developing new vaccines. “We need to make the case that we need this, and then develop it for regulatory review, sharing data with FDA (Food and Drug Administration) and everybody else,” he says. “We need to think of this pandemic as if we are already at a near point in the future. It’s sort of a thought experiment, but if we may need it, we better be working on it. If a fourth [vaccine] dose doesn’t prevent infection in Israel then it is probably not going to anywhere else.”
To the latter point, Israel has reported disappointing results for its fourth shot (or second booster). Researchers at Sheba Medical Center have reported some early findings of a small study of the efficacy of the efficacy of a fourth Pfizer shot in about 150 healthcare workers. They had not published the study as this report was filed.
“What we see is that after two weeks, the Pfizer vaccine gives an enhancement or increase in the number of antibodies, including neutralizing antibodies,” said Gili Regev-Yochay, MD, a lead researcher said at a press conference.1 “[But it is] probably not enough for Omicron.”
That initial take-home point appears to be that the fourth booster could help prevent serious disease but not initial infection.
“[The] increase in antibodies [is] higher than after the third dose,” Regev-Yochay said.2 “[However], we see many infected with Omicron who received the fourth dose. Granted, a bit less than in the control group, but still a lot of infections.”
Third Shot Strong, but Fades
The United States has announced no plans for a fourth shot, but the third-shot booster clearly provides a greater level of protection against emergency care and hospitalization during both Delta dominance and the ascension of Omicron, the Centers for Disease Control and Prevention (CDC) reported.3
During both Delta- and Omicron-predominant periods, receipt of the third-shot booster dose was “highly effective” at preventing COVID-19-associated emergency department (ED) and urgent care (UC) visits and hospitalizations, the CDC found.
The CDC did a 10-state analysis of 222,772 ED and UC encounters, along with 87,904 hospitalizations, among adults with COVID-19-like illness from Aug. 26, 2021, to Jan. 5, 2022. Vaccine efficacy declined as Omicron became the dominant variant, but the third-shot booster staved off a lot of severe disease.
During both Delta- and Omicron-predominant periods, receipt of a third vaccine dose was highly effective at preventing COVID-19-associated ED and UC encounters (94% and 82%, respectively) and preventing COVID-19-associated hospitalizations (94% and 90%, respectively).
In a separate CDC study in Los Angeles County during Omicron predominance, COVID-19 incidence among unvaccinated people was four times greater than those vaccinated and boosted.4 Hospitalization rates were 23 times greater among the unvaccinated.
However, a recent pre-print study found that immunity begins to degrade four months after the third booster.
“While vaccine effectiveness against symptomatic infection due to Omicron may wane following a third dose of BNT162b2 [Pfizer-BioNTech] the effectiveness against hospitalization remains high,” the authors noted.5 Israel was well aware of waning issues, justifying the pursuit of a fourth shot.6
Both Pfizer and Moderna have Omicron-specific vaccines in clinical trials, but their efficacy or the degree to which a new variant could undermine it are open questions. Meanwhile, Moderna’s original vaccine has met final public health approvals for marketing as “Spikevax,” giving the United States two fully approved vaccines.
Unfortunately, they do not completely prevent breakthrough infections with Omicron, which is expected to continue to circulate globally unless another variant dethrones it.
“COVID is not going away,” says William Schaffner, MD, an infectious disease and vaccine expert at Vanderbilt University in Nashville, TN. “We’re going to have to develop a chronic, endemic COVID strategy, the way we do with flu. [This could] be a twice-a-year assessment — like our annual influenza vaccine — one for the Southern Hemisphere, one for the North. That kind of booster might be a mixture of Omicron plus some antigen from other variants. That all has to be determined, and lot will depend on if another variant appears out there somewhere.”
‘Sobering Facts’
The fear that another variant could emerge — one with enough evolutionary advantages to vanquish Omicron — has added urgency to calls for a more universal vaccine.
David Morens, MD, is the lead author of a recent paper underscoring the need universal coronavirus vaccines, in part because of Omicron’s ability to break through natural immunity or vaccination.
“These sobering facts suggest that SARS-CoV-2 is unlikely to be eliminated, let alone eradicated; it will probably continue to circulate indefinitely in periodic outbreaks and endemics,” Morens and colleagues warn.7 “Meanwhile, an unknown number of animal coronaviruses, of unknown transmissibility and lethality, may well emerge in the foreseeable future. We must therefore greatly accelerate our efforts in coronavirus vaccinology.”
In a podcast accompanying the article, Morens said the key to these new vaccines is in “a small part of the tree of coronavirus” — a subgenus of coronaviruses called sarbecoviruses.
“The reservoir in nature for all of these sarbecoviruses — SARS (severe acute respiratory syndrome)-like viruses — is in bats, particularly Rhinolophus [horseshoe] bats that exist in Southeast Asia and contiguous parts of Southern and Southwest China,” said Morens, a virologist and epidemiologist at the National Institute of Health’s National Institute of Allergy and Infectious Diseases.
There are many sarbecoviruses, and they commonly spillover from bats to other mammals, creating the scenario for mutation and eventual human infection, such as what occurred with the original SARS and Middle East respiratory syndrome (MERS) in the Middle East, both of which appeared in the last 20 years, he explained.
“That would suggest that these emergences are becoming more likely and, certainly, more deadly, since the viruses we’ve seen now, like SARS-CoV-2, are more deadly than the endemic coronaviruses that emerged in the past,” Morens said. It will take international coordination to research these viruses, which could hold the key to a universal coronavirus vaccine.
“These viruses are in places that are unique and restricted geographically,” he said. “[But] that’s where the ‘money’ is — the most important clues, the viral sequences and so on, that will help us in vaccine development.”
Could ‘Hurt Us as a Species’
If vaccines with broad efficacy are not developed, we could eventually face a variant that surpassed Omicron to completely escape human immunity.
“Then we’re back at ground zero,” Morens said. “If that happens, we’re back to where we were in early 2020 when we had a brand-new pandemic and no vaccines.”
Concurring on this need for broadly effective vaccines is Eric Topol, MD, a professor of molecular medicine and director and founder of the Scripps Research Translational Institute in La Jolla, CA.
“If our vaccines weren’t holding up, we’d be in big, big trouble right now,” he said in a recent interview at the University of California-San Francisco (UCSF).8 “We may not be so lucky the next time. If there’s one way to hurt us as a species with this virus, it would be immune escape.”
Omicron has been a master of immune escape and causing breakthrough infections, but its emergence was not predictable, and neither is the variant that could arise to overthrow it, Topol emphasized.
“We could not have predicted this hypermutated Omicron — no matter what AI (artificial intelligence) tool you have, or human intelligence,” he said. “These specific mutations that are littered all over the virus — not just in the RBD (receptor-binding domain) and the spike, but throughout the virus — no one could have predicted this. All the experts of viral evolution pretty much thought it would be a Delta-plus, and then came this curveball, Omicron.”
In a paper published last year, Topol called for “pan-sarbecovirus or pan-beta coronavirus vaccines. That’s what we should have in clinical trials right now. There is one at Walter Reed that is getting into Phase II, but we should have multicandidate clinical trials — an equivalent of Operation Warp Speed, to protect us against a possible worse-than-Omicron variant.”9
REFERENCES
- Jeffay N. Israeli study on 4th shots for COVID is bad news — but not as bad as it seems. The Times of Israel. Published Jan. 18, 2022. https://www.timesofisrael.com/israeli-study-on-4th-shots-for-covid-is-bad-news-but-not-as-bad-as-it-seems/
- TOI staff. Israeli trial, world’s first, finds 4th dose ‘not good enough’ against Omicron. The Times of Israel. Published Jan. 17, 2022. https://www.timesofisrael.com/israeli-trial-worlds-first-finds-4th-dose-not-good-enough-against-omicron/
- Thompson MG, Natarajan K, Irving SA, et al. Effectiveness of a third dose of mRNA vaccines against COVID-19-associated emergency department and urgent care encounters and hospitalizations among adults during periods of Delta and Omicron variant predominance — VISION Network, 10 states, August 2021-January 2022. MMWR Morb Mortal Wkly Rep 2022;71:139-145.
- Danza P, Koo TH, Haddix M, et al. SARS-CoV-2 infection and hospitalization among adults aged >/= 18 years, by vaccination status, before and during SARS-CoV-2 B.1.1.529 (Omicron) variant predominance — Los Angeles County, California, November 7, 2021-January 8, 2022. MMWR Morb Mortal Wkly Rep 2022;71:177-181.
- Xia H, Zou J, Kurhade C, et al. Neutralization of Omicron SARS-CoV-2 by 2 or 3 doses of BNT162b2 vaccine. bioRxiv 2022; Jan 22. preprint Jan. 22, 2022. doi: https://doi.org/10.1101/2022.01.21.476344. [Preprint].
- Goldberg Y, Mandel M, Bar-On YM, et al. Waning immunity after the BNT162b2 vaccine in Israel. N Engl J Med 2021;385:e85.
- Morens DM, Taubenberger JK, Fauci AS. Universal coronavirus vaccines — An urgent need. N Engl J Med 2022;386:297-299.
- YouTube. The Omicron whirlwind: A conversation with Eric Topol - The current and future state of the pandemic. UCSF Department of Medicine. Published Jan. 13, 2022. https://www.youtube.com/watch?v=lCAvFHd3B38&t=123s
- Burton DR, Topol EJ. Variant-proof vaccines — Invest now for the next pandemic. Nature 2021;590:386-388.
There is an emerging consensus in the scientific community that is two-fold: COVID-19 is not going away anytime soon, and continuous vaccine boosters eventually could yield diminishing returns. What is needed are new, second-generation vaccines that confer broader immunity against both circulating variants and mutations yet to arise.
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