COVID-19 Vaccines Vs Variants—Determining How Much Immunity Is Enough

News & Analysis

Medical News & Perspectives COVID-19 Vaccines vs Variants—Determining How Much Immunity Is Enough

Rita Rubin, MA

s COVID-19 cases resulting from infection with SARS-CoV-2 variants A accumulate in the US and around the world, one question looms large: How well do the COVID-19 vaccines developed so far protect against these novel coronavirus spinoffs? “The virus is telling us it’s going to throw out a lot of mutations,” infectious disease specialist Jesse Goodman, MD, MPH, who, as then-chief scientist at the US Food and Drug Administration (FDA), led the agency’s response to the H1N1 influenza A pan- demic, said in an interview. “Even if we don’t have a critical situation right at the moment- …there’s a realistic possibility that variants will continue to evolve that have potential to avoid vaccine immunity.” That’s to be expected, Anthony Fauci, MD, director of the National Institute of Al- lergy and Infectious Diseases (NIAID), told JAMA Editor in Chief Howard Bauchner, MD, in a February 3 podcast. Regardless of the platform on which the vaccine is based, Fauci said, “you still have a fixed immunogen and avirusthat’schanging.Soonerorlater,you’re When viruses replicate, Penn State bi- mutations in the spike protein, spurring vac- going to get a mutant that evades that.” ologist David Kennedy,PhD, explained in an cine efficacy concerns. One reason SARS-CoV-2 is throwing out interview, the cycle is like a classic child- Trials of the Novavax, Janssen/Johnson variants and will continue to do so is be- hood game. “Viruses copying themselves, & Johnson, and AstraZeneca vaccines in cause relatively few people globally have it’s almost like a game of telephone,” said South Africa, where the B.1.351 variant of been vaccinated, Norman Baylor, PhD, a for- Kennedy, who studies pathogen evolution. concern represents virtually all of the circu- mer director of the FDA’s Office of Vaccines “They repeat what they thought they heard, lating SARS-CoV-2, seemed to justify those Research and Review, noted in an inter- so they make mistakes all the time.” concerns. The South Africa trials found lower view. “This virus is like, ‘Yep, I’ve got plenty Despite those many mistakes, Kennedy vaccineefficacycomparedwithtrialsinother of people I can infect, and the more I repli- noted, he’s unaware of any vaccines against countries where B.1.351 wasn’t dominant. cate, the more I can mutate,’” Baylor said. viral diseases other than seasonal flu that The pivotal trials of the Pfizer-BioNTech Some scientists have used the term have had to be updated because of changes and Moderna vaccines, the first 2 autho- vaccine resistance to describe the reduced in the virus. Hepatitis B virus developed rized by the FDA, were conducted mainly in efficacy of COVID-19 vaccines against some “vaccine escape mutations,”but they posed the US before any cases of infection by variants. But that confuses matters by sug- no health risks, he said. B.1.351 or other variants of concern had been gesting vaccines are analogous to antibiot- detected in the country. ics, University of Washington biologist Carl Good Enough? Much of the current data on the mes- Bergstrom, PhD, who studies evolution and Current COVID-19 vaccines are based on the senger RNA (mRNA) vaccines’ efficacy medicine, said in an interview.“The key point SARS-CoV-2 spike protein, which the virus against SARS-CoV-2 variants has come from for me is that in antibiotic resistance, the uses to bind to and infect host cells, of the laboratory studies in which researchers ex- changes happen in people who are on anti- original Wuhan-hu-1. But the emerging “vari- posed serum samples from immunized in- biotics,” he said, while antigenic escape by ants of concern”—deemed so because they dividuals to genetically engineered ver- SARS-CoV-2 occurs in people who haven’t appear to be more transmissible or deadlier sions of concerning variants and then been vaccinated. than the wild-type SARS-CoV-2—contain measured neutralizing antibody titers. Such

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studies repeatedly have shown the vac- Johnson & Johnson’s adenovirus-based vac- Goodman concurred. “It’s consistent cines elicit lower levels of neutralizing anti- cine, which the FDA authorized for emer- with how the immune system works,” bodies against SARS-CoV-2 variants than gency use on February 27,suggest that neu- he said, explaining that although protection against older, more common isolates. tralization correlates with protection but against B.1.351 might be incomplete, Forexample,inaFebruary17lettertothe probably is not the only biomarker that does, vaccines could still protect against severe editorinTheNewEnglandJournalofMedicine, Johan Van Hoof, MD, who oversees vaccine COVID-19. In regard to the Oxford- scientists described testing serum samples research and development at Janssen, AstraZeneca vaccine, he said, “my guess is from individuals immunized with 2 doses of a Johnson & Johnson subsidiary, said it will be like the other vaccines and have thePfizer-BioNTechvaccineagainstrecombi- February 26 during an FDA advisory com- some effect” against B.1.351. nantvirusescontainingsomeorallofthespike mittee meeting. As Baylor, a consultant on vaccines for proteinmutationsfoundintheB.1.351variant. the World Health Organization, noted, “One Neutralization of B.1.351 was approximately Experiments vs Experience of the biggest things you want to do in a pan- two-thirdslowerthanthatofUSA-WA1/2020, Without immune correlates of protection, demic is keep people from dying and keep an early SARS-CoV-2 isolate. only real-world experience can provide them out of the hospital.” In another letter published the same answers about COVID-19 vaccines’ effi- That appears to be happening. day, researchers reported measuring neu- cacy against illness and death from SARS- COVID-19 cases and hospitalizations tralizing antibody activity in serum samples CoV-2 variants. started to decline in mid-January in Israel, from participants in the phase 1 trial of the “For right now, you know that a line is which leads the world in percentage of the Moderna COVID-19 vaccine. One week af- crossed if you see people fully immunized population vaccinated. Larger and earlier ter the participants received the second with the vaccines [who], nonetheless, when decreases occurred among older individu- dose, neutralizing antibody titers induced by infected with the variants, are being hospi- als, who were a top priority for vaccination, a recombinant virus bearing the B.1.351 spike talized,” Offit said at a February 4 COVID-19 according to an article posted February 9 protein were 6-fold lower than those in- Vaccine Analysis Team press briefing. that had not been peer reviewed. In the duced by a recombinant virus bearing the At first glance, findings from a phase 2 week before the study was posted, COVID- original Wuhan-Hu-1 spike protein. trial of the Oxford-AstraZeneca vaccine in 19–related hospitalizations declined by However, that still might be sufficient South Africa seemed quite discouraging, 36% and 29% fewer patients were severely to protect against COVID-19, or at least se- spurring that country to suspend its planned ill with COVID-19 than 3 weeks earlier. The vere COVID-19. rollout of the vaccine. The trial found that the B.1.1.7 variant, first identified in the UK, is “Fortunately, neutralization titers in- vaccine did not protect against mild to mod- now the dominant SARS-CoV-2 variant in duced by vaccination are high, and even with erate COVID-19 caused by the B.1.351 vari- Israel as well as in the UK. That variant a 6-fold decrease, serum can still effec- ant. The findings, posted February 12, had doesn’t appear to reduce neutralizing anti- tively neutralize the virus,”Fauci and 2 NIAID not been peer reviewed. bodies to the same extent as B.1.351. colleagues wrote in a JAMA editorial posted However, “the study was not really de- Similarly encouraging UK data, al- February 11. And, they noted, lower vaccine signed to determine whether the vaccine though not peer reviewed, were posted efficacy in the South African clinical trials could protect against severe COVID or not,” in February. could be related to geographic or popula- principal investigator Shabir Madhi, MBBCH, In Scotland, researchers estimated that tion differences. PhD, a vaccinologist at the University of the Pfizer-BioNTech’s vaccine was up to 85% ef- Although serum antibody levels corre- Witwatersrand, Johannesburg, and co- fective and Oxford-AstraZeneca’s vaccine up late well with protection for many infectious founder and codirector of the African Lead- to 94% effective in preventing COVID-19– diseases, protective levels haven’t yet been ership Initiative for Vaccinology Expertise, related hospitalizations 28 to 34 days after determined for SARS-CoV-2. They may never said in a February 7 briefing about the re- a single dose—the UK policy is to provide the be established, Baylor said. “With some or- sults. Participants, who numbered only second dose 12 weeks later. ganisms, it’s very difficult to pinpoint exactly about 2000, were young—average age 31 A Public Health England (PHE) report on what level of [antibody] response is needed,” years—and healthy,so their risk of severe dis- immunization with the Oxford-AstraZeneca he said, citing the bacterium that causes ease was low, vaccinated or not, explained or Pfizer-BioNTechvaccine noted that “early pertussis as one such microbe. Madhi, who also led Novavax’s vaccine trial data suggest that any cases that do occur in In addition to neutralizing antibodies, in South Africa. older vaccinated people are around half as mRNA vaccines also induce virus-specific Novavax and Janssen conducted larger likely to lead to hospitalisation and/or death.” helper T cells and cytotoxic T cells that trials in South Africa than Oxford and The data came from those vaccinated only might help protect against infection, Paul AstraZeneca. Although both of their vac- 14 days earlier; lower rates of hospitaliza- Offit, MD, director of the Children’s Hospi- cines had lower efficacy rates in South Africa tion and death would likely be seen in people tal of Philadelphia’s Vaccine Education than in trials in other countries, vaccinated vaccinated more than 3 or 4 weeks earlier, Center, and John Moore, PhD, a microbiolo- participants who received the Janssen vac- the report noted. gist and immunologist at Weill Medical Col- cine were still less likely to require hospital- lege of Cornell University, noted in a JAMA ization for COVID-19 than those who re- Stopping the Spread viewpoint published recently. ceived placebo shots, and Madhi recently The US Centers for Disease Control and Pre- Assays of serum samples from partici- told Nature he expected that to be the case vention advises that even after they’re fully pants in the phase 1 and phase 3 trials of with the Novavax vaccine as well. vaccinated, people should continue to mask

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up and socially distance in public places in they’re both RNA viruses, “the backdrop is On February 22, the FDA updated its partbecausetheycouldstillunknowinglybe- so different,” Baylor said. “We are in a pan- nonbinding guidance for vaccine manufac- come infected and, although asymptom- demic. We didn’t have a vaccine. This [mRNA turers to include information about what the atic, transmit SARS-CoV-2 to people who vaccines] is new technology.” agency would like to see when evaluating haven’t yet received their shots. Short of developing a universal vaccine vaccines that have been modified to ad- Transmission by infected asymptom- that protects against most SARS-CoV-2 vari- dress emerging SARS-CoV-2 variants. atic vaccinees could provide an opportu- ants, “we need to be prepared to make al- The updated guidance advises manu- nity for more virulent variants to spread, terations in the existing [COVID-19] vac- facturers to conduct studies comparing Kennedy suggested in a 2015 article. The ar- cines to deal with [variants] that emerge,” neutralizing antibody responses to SARS- ticle described an experiment with a her- Goodman said. CoV-2 induced by the modified vaccine pes virus that causes Marek disease in chick- Out of what they call an abundance of with those induced by the prototype vac- ens. Vaccines against Marek disease are caution, manufacturers say they’re devel- cine. One such study should use serum described as “leaky” because, although they oping strategies to deal with the possibility samples from people who hadn’t been pre- protectchickensfromgettingsick,theydon’t of a variant that escapes coverage by first- viously vaccinated or infected with SARS- prevent them from becoming infected and generation vaccines. CoV-2, while another study would use transmitting the virus to unvaccinated chick- At the February 26 FDA advisory com- serum samples from people previously vac- ens.Thatallowsthemostvirulentstrainsthat mittee meeting, Van Hoof said Janssen plans cinated with a prototype vaccine who then normally would die along with an infected to launch a phase 1 trial of a SARS-CoV-2 vari- received an experimental booster against chicken to survive and infect and kill unvac- ants vaccine by this summer. variants of concern. cinated chickens, the experiment found. Pfizer and BioNTech announced Febru- Fortunately, as the article notes, nearly ary 25 that they had begun evaluating the The Hard Part all vaccines used in humans prevent asymp- safety and immunogenicity of a third dose Modifying COVID-19 vaccines would prob- tomatic infection and spread. of their vaccine to see whether it would ably be the most straightforward step in “In general, vaccines that are effec- boost immunity to SARS-CoV-2 variants. In dealing with SARS-CoV-2 variants. “For vac- tive in reducing infections do have major addition, the companies said they are dis- cines and biologics, it’s the manufacturing impacts on reducing transmission,” said cussing with regulatory agencies, including process that defines the product, and the Goodman, director of Georgetown Univer- the FDA, a clinical study to evaluate a modi- manufacturing process isn’t changing,” sity’s Center on Medical Product Access, fied vaccine based on the B.1.351 variant. Baylor explained. Safety and Stewardship. “It is probable that “The companies are hoping to pursue the More challenging will be deciding when these vaccines will reduce transmission.” validation of future modified mRNA vac- and how to deploy COVID-19 vaccines 2.0. Mounting evidence supports that no- cines with a regulatory pathway similar to The influenza model, in which surveillance tion. In a study of UK health care workers im- what is currently in place for flu vaccines,”ac- during the Southern Hemisphere’s flu sea- munized with the Pfizer-BioNTech vaccine, cording to a press release. son identifies the circulating strains to tar- participants underwent biweekly poly- Moderna announced February 24 that get with vaccines in the Northern Hemi- merase chain reaction testing and twice it had shipped a booster vaccine candidate sphere’s coming flu season, doesn’t work for weekly rapid antigen testing to help inves- based on B.1.351 to the NIAID for a phase 1 SARS-CoV-2, Baylor noted. tigators determine rates of asymptomatic trial. And Novavax, whose first-generation “The challenge for COVID is what vari- and symptomatic infections. vaccine hasn’t been authorized yet in the US, ant do you pick” when modifying a vaccine, The study, posted February 22 but not announced January 28 it was working on de- he said. “How often does it change?” peer reviewed, found a 70% reduction in veloping a booster, a combination bivalent Once that’s decided, would people both types of infection 21 days after partici- vaccine, or both to protect against variants. who’ve already received the original pantsreceivedtheirfirstdoseandan85%re- The company said it expected to begin clini- COVID-19 vaccine get a booster shot to pro- duction a week after receiving their second cal trials in the second quarter of 2021. tect against variants of concern while vac- dose. “Overall, we’re seeing a really strong ef- Modifying vaccines to target variants cine-naive individuals receive the original fect to reducing any infection—asymptom- isn’t difficult. For example, with Pfizer- vaccine and the booster rolled into one? “Do atic and symptomatic,” coauthor Susan BioNTech’s and Moderna’s mRNA vaccines, we have the capacity to make both?” Baylor Hopkins, MD, PHE strategic response direc- “it’s very convenient, because, basically, all asked. tor,saidatapressconference.InMarch,Pfizer you do is change a computer program and Plus, the need to deploy vaccines or and BioNTech announced that non–peer- the synthetic for the synthesizing portion of boosters targeting new variants would com- reviewed data from Israel showed their vac- this and you can change the vaccine,” Peter plicate the already rocky rollout of COVID-19 cine was 94% effective against asymptom- Marks, MD, PhD, director of the FDA’s Cen- vaccines, in part due to inexperience in vac- atic SARS-CoV-2 infection. ter for Biologics Evaluation and Research, cinating US adults en masse. which regulates vaccines, said during a Janu- “How do we deploy this?” Baylor said of Next Steps ary 29 American Medical Association (AMA) next-generation COVID-19 vaccines. “When Whether COVID-19 will join influenza as an webinar. “But the question is, what do we do we pull the trigger to actually do this?”

infectious disease for which annual vaccina- need from the FDA perspective to feel com- Note: Source references are available through tion is required isn’t yet known. Although fortable having that deployed.” embedded hyperlinks in the article text online.

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