Virus World

Background: During Late 2022, the SARS-CoV-2 Omicron BA.5 sublineages accounted for most of the sequenced viral genomes worldwide. Bivalent mRNA vaccines contain an ancestral SARS-CoV-2 strain component plus an updated component of the Omicron BA.4/BA.5. Since September 2022, a single bivalent booster dose has been recommended for adults who have completed a primary vaccination series and are at high risk for severe Covid-19 disease. Evidence regarding the effectiveness of the bivalent vaccine in reducing hospitalizations and death due to Covid-19 is warranted.

Methods: This retrospective cohort study included all members of Clalit Health Services, aged ≥65, eligible for a bivalent booster. Hospitalizations and death due to Covid-19 among participants who received the bivalent vaccine were compared with those who did not. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between the bivalent vaccine and Covid-19 outcomes while adjusting for demographic factors and coexisting illnesses.

Findings: A total of 622,701 participants met the eligibility criteria. Of those, 85,314 (14%) received a bivalent-booster during the 70-day study period. Hospitalization due to Covid-19 occurred in 6 bivalent recipients and 297 participants who did not, adjusted hazard ratio (HR): 0.19 (95% CI, 0.08-0.43). Death due to Covid-19 occurred in 1 bivalent recipient and 73 participants who did not, adjusted HR 0.14: (95% CI, 0.02-1.04).

Interpretation: Participants who received the bivalent vaccine had lower hospitalization and mortality rates due to Covid-19 than non-recipients up to 70 days after vaccination.
Funding Information: None.

Preprint available at the Lancet:

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4314067 

The BA.2.75* sublineage of SARS-CoV-2 B.1.1.529 (omicron) variant escapes neutralizing antibodies. We estimated effectiveness of prior infection in preventing reinfection with BA.2.75* using a test-negative, case-control study design. Effectiveness of prior pre-omicron infection against BA.2.75* reinfection, irrespective of symptoms, was 6.0% (95% CI: 1.5-10.4%). Effectiveness of prior BA.1/BA.2 infection was 49.9% (95% CI: 47.6-52.1%) and of prior BA.4/BA.5 infection was 80.6% (95% CI: 71.2-87.0). Effectiveness of prior pre-omicron infection followed by BA.1/BA.2 infection against BA.2.75* reinfection was 56.4% (95% CI: 50.5-61.6). Effectiveness of prior pre-omicron infection followed by BA.4/BA.5 infection was 91.6% (95% CI: 65.1-98.0).

Analyses stratified by time since prior infection indicated waning of protection since prior infection. Analyses stratified by vaccination status indicated that protection from prior infection is higher among those vaccinated, particularly among those who combined index-virus-type vaccination with a prior omicron infection. A combination of pre-omicron and omicron immunity is most protective against BA.2.75* reinfection. Viral immune evasion may have accelerated recently to overcome high immunity in the global population, thereby also accelerating waning of natural immunity.

Preprint available in medRxiv (Oct. 30, 2022):

https://doi.org/10.1101/2022.10.29.22281606 

Israelis who had an infection were more protected against the Delta coronavirus variant than those who had an already highly effective COVID-19 vaccine. The natural immune protection that develops after a SARS-CoV-2 infection offers considerably more of a shield against the Delta variant of the pandemic coronavirus than two doses of the Pfizer-BioNTech vaccine, according to a large Israeli study that some scientists wish came with a “Don’t try this at home” label. The newly released data show people who once had a SARS-CoV-2 infection were much less likely than vaccinated people to get Delta, develop symptoms from it, or become hospitalized with serious COVID-19.  The study demonstrates the power of the human immune system, but infectious disease experts emphasized that this vaccine and others for COVID-19 nonetheless remain highly protective against severe disease and death. And they caution that intentional infection among unvaccinated people would be extremely risky. “What we don’t want people to say is: ‘All right, I should go out and get infected, I should have an infection party.’” says Michel Nussenzweig, an immunologist at Rockefeller University who researches the immune response to SARS-CoV-2 and was not involved in the study. “Because somebody could die.” The researchers also found that people who had SARS-CoV-2 previously and then received one dose of the Pfizer-BioNTech messenger RNA (mRNA) vaccine were more highly protected against reinfection than those who once had the virus and were still unvaccinated. The study, conducted in one of the most highly COVID-19–vaccinated countries in the world, examined medical records of tens of thousands of Israelis, charting their infections, symptoms, and hospitalizations between 1 June and 14 August, when the Delta variant predominated in Israel. It’s the largest real-world observational study so far to compare natural and vaccine-induced immunity to SARS-CoV-2, according to its leaders.

The research impresses Nussenzweig and other scientists who have reviewed a preprint of the results, posted yesterday on medRxiv. “It’s a textbook example of how natural immunity is really better than vaccination,” says Charlotte Thålin, a physician and immunology researcher at Danderyd Hospital and the Karolinska Institute who studies the immune responses to SARS-CoV-2 . “To my knowledge, it’s the first time [this] has really been shown in the context of COVID-19.” Still, Thålin and other researchers stress that deliberate infection among unvaccinated people would put them at significant risk of severe disease and death, or the lingering, significant symptoms of what has been dubbed Long Covid. The study shows the benefits of natural immunity, but “doesn’t take into account what this virus does to the body to get to that point,” says Marion Pepper, an immunologist at the University of Washington, Seattle. COVID-19 has already killed more than 4 million people worldwide and there are concerns that Delta and other SARS-CoV-2 variants are deadlier than the original virus. The new analysis relies on the database of Maccabi Healthcare Services, which enrolls about 2.5 million Israelis. The study, led by Tal Patalon and Sivan Gazit at KSM, the system’s research and innovation arm, found in two analyses that people who were vaccinated in January and February were, in June, July, and the first half of August, six to 13 times more likely to get infected than unvaccinated people who were previously infected with the coronavirus. In one analysis, comparing more than 32,000 people in the health system, the risk of developing symptomatic COVID-19 was 27 times higher among the vaccinated, and the risk of hospitalization eight times higher. “The differences are huge,” says Thålin, although she cautions that the numbers for infections and other events analyzed for the comparisons were “small.” For instance, the higher hospitalization rate in the 32,000-person analysis was based on just eight hospitalizations in a vaccinated group and one in a previously infected group. And the 13-fold increased risk of infection in the same analysis was based on just 238 infections in the vaccinated population, less than 1.5% of the more than 16,000 people, versus 19 reinfections among a similar number of people who once had SARS-CoV-2. No one in the study who got a new SARS-CoV-2 infection died—which prevented a comparison of death rates but is a clear sign that vaccines still offer a formidable shield against serious disease, even if not as good as natural immunity. Moreover, natural immunity is far from perfect. Although reinfections with SARS-CoV-2 are rare, and often asymptomatic or mild, they can be severe.

In another analysis, the researchers compared more than 14,000 people who had a confirmed SARS-CoV-2 infection and were still unvaccinated with an equivalent number of previously infected people who subsequently received one dose of the Pfizer-BioNTech vaccine. (In Israel, it’s recommended that people who have been previously infected get just one dose.) The team found that the unvaccinated group was twice as likely to be reinfected as the singly vaccinated. “We continue to underestimate the importance of natural infection immunity … especially when [infection] is recent,” says Eric Topol, a physician-scientist at Scripps Research. “And when you bolster that with one dose of vaccine, you take it to levels you can’t possibly match with any vaccine in the world right now.” Nussenzweig says the results in previously infected, vaccinated people confirm laboratory findings from a series of papers in Nature and Immunity by his group, his Rockefeller University colleague Paul Bieniasz and others—and from a preprint posted this month by Bieniasz and his team. They show, Nussenzweig says, that the immune systems of people who develop natural immunity to SARS-CoV-2 and then get vaccinated produce exceptionally broad and potent antibodies against the coronavirus. The preprint, for example, reported that people who were previously infected and then vaccinated with an mRNA vaccine had antibodies in their blood that neutralized the infectivity of another virus, harmless to humans, that was engineered to express a version of the coronavirus spike protein that contains 20 concerning mutations. Sera from vaccinated and naturally infected people could not do so. As for the Israel medical records study, Topol and others point out several limitations, such as the inherent weakness of a retrospective analysis compared with a prospective study that regularly tests all participants as it tracks new infections, symptomatic infections, hospitalizations, and deaths going forward in time. “It will be important to see these findings replicated or refuted,” says Natalie Dean, a biostatistician at Emory University. She adds: “The biggest limitation in the study is that testing [for SARS-CoV-2 infection] is still a voluntary thing—it’s not part of the study design.” That means, she says, that comparisons could be confounded if, for example, previously infected people who developed mild symptoms were less likely to get tested than vaccinated people, perhaps because they think they are immune. Nussenzweig’s group has published data showing people who recover from a SARS-CoV-2 infection continue to develop increasing numbers and types of coronavirus-targeting antibodies for up to 1 year. By contrast, he says, twice-vaccinated people stop seeing increases “in the potency or breadth of the overall memory antibody compartment” a few months after their second dose. For many infectious diseases, naturally acquired immunity is known to be more powerful than vaccine-induced immunity and it often lasts a lifetime. Other coronaviruses that cause the serious human diseases severe acute respiratory syndrome and Middle East respiratory syndrome trigger robust and persistent immune responses. At the same time, several other human coronaviruses, which usually cause little more than colds, are known to reinfect people regularly.

Study Cited Available in medRxiv (August 25, 2021):

https://doi.org/10.1101/2021.08.24.21262415 

You might assume that 95 out of every 100 people vaccinated will be protected from Covid-19. But that’s not how the math works. The front-runners in the vaccine race seem to be working far better than anyone expected: Pfizer and BioNTech announced this week that their vaccine had an efficacy rate of 95 percent. Moderna put the figure for its vaccine at 94.5 percent. In Russia, the makers of the Sputnik vaccine claimed their efficacy rate was over 90 percent. “These are game changers,” said Dr. Gregory Poland, a vaccine researcher at the Mayo Clinic. “We were all expecting 50 to 70 percent.” Indeed, the Food and Drug Administration had said it would consider granting emergency approval for vaccines that showed just 50 percent efficacy. From the headlines, you might well assume that these vaccines — which some people may receive in a matter of weeks — will protect 95 out of 100 people who get them. But that’s not actually what the trials have shown. Exactly how the vaccines perform out in the real world will depend on a lot of factors we just don’t have answers to yet — such as whether vaccinated people can get asymptomatic infections and how many people will get vaccinated.  Here’s what you need to know about the actual effectiveness of these vaccines.

What do the companies mean when they say their vaccines are 95 percent effective?

The fundamental logic behind today’s vaccine trials was worked out by statisticians over a century ago. Researchers vaccinate some people and give a placebo to others. They then wait for participants to get sick and look at how many of the illnesses came from each group. In the case of Pfizer, for example, the company recruited 43,661 volunteers and waited for 170 people to come down with symptoms of Covid-19 and then get a positive test. Out of these 170, 162 had received a placebo shot, and just eight had received the real vaccine. From these numbers, Pfizer’s researchers calculated the fraction of volunteers in each group who got sick. Both fractions were small, but the fraction of unvaccinated volunteers who got sick was much bigger than the fraction of vaccinated ones. The scientists then determined the relative difference between those two fractions. Scientists express that difference with a value they call efficacy. If there’s no difference between the vaccine and placebo groups, the efficacy is zero. If none of the sick people had been vaccinated, the efficacy is 100 percent. A 95 percent efficacy is certainly compelling evidence that a vaccine works well. But that number doesn’t tell you what your chances are of becoming sick if you get vaccinated. And on its own, it also doesn’t say how well the vaccine will bring down Covid-19 across the United States.

What’s the difference between efficacy and effectiveness?

Efficacy and effectiveness are related to each other, but they’re not the same thing. And vaccine experts say it’s crucial not to mix them up. Efficacy is just a measurement made during a clinical trial. “Effectiveness is how well the vaccine works out in the real world,” said Naor Bar-Zeev, an epidemiologist at the Johns Hopkins Bloomberg School of Public Health. It’s possible that the effectiveness of coronavirus vaccines will match their impressive efficacy in clinical trials. But if previous vaccines are any guide, effectiveness may prove somewhat lower. The mismatch comes about because the people who join clinical trials are not a perfect reflection of the population at large. Out in the real world, people may have a host of chronic health problems that could interfere with a vaccine’s protection, for example. The Centers for Disease Control and Prevention has a long history of following the effectiveness of vaccines after they’re approved. On Thursday, the agency posted information on its website about its plans to study the effectiveness of coronavirus vaccines. It will find opportunities to compare the health of vaccinated people to others in their communities who have not received a vaccine....

The BCCDC says this year's vaccine appears to cut the risk of medically attended influenza-like illness by more than half, with an estimated vaccine effectiveness of 55 per cent. The BC Centre for Disease Control says early evaluation shows this year’s influenza vaccine formula is providing “substantial” protection against the wave of flu so far. “The earlier-than-usual influenza epidemic this season has enabled us to assess vaccine effectiveness earlier than usual,” BC CDC epidemiologist and Canadian Sentinel Practitioner Surveillance Network lead Dr. Danuta Skowronski said. “We will update our analyses in the new year, but these interim findings show a substantial reduction in the risk of influenza illness for vaccinated people who seek medical care.” Analysis for the period from Nov. 1 to Dec. 14 with samples from B.C., Alberta, Ontario and Quebec had cut the risk of medically attended influenza-like illness by more than half, with an estimated vaccine effectiveness of 55 per cent. An update from the BCCDC on Thursday also showed there had been no additional flu-related deaths among children and youth this season. Six people under the age of 18 have died so far this year, several due to suspected influenza-linked bacterial infections. That same update showed that the epidemic wave appears to be waning. About 16 per cent of samples over the week ending Dec. 17 came back positive — down from a high of 27 per cent during the week ending Nov. 26.

The BCCDC’s latest analysis shows the number of tests that came back positive for RSV for the week ending Dec. 17 jumped to 13 per cent, up from six per cent in the week ending Nov. 26. Test-positivity for both RSV (37 per cent) and influenza A (21 per cent) remains higher among children and youth younger than 18 than in the general population, the BCCDC said. According to the BCCDC, the H3 subtype of influenza A remains the dominant strain of influenza this year, accounting for more than 90 per cent of tested samples. The H3N2 subtype is often linked to more severe outbreaks and lower vaccine effectiveness, however, this year’s vaccine appears to be as good as or better than in previous years the subtype was dominant, the agency said. “Vaccine protection is especially important for people at higher risk of severe complications and for a health-care system that is managing the circulation of multiple respiratory viruses at the same time as we enter the holiday period,” Skowronski said. The province continues to recommend vaccines for anyone aged six months and older, and is urging anyone who feels unwell to stay home.

US CDC historical data on influenza vaccine effectiveness in past seasons available at: 

https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html 

Background: Whether vaccine effectiveness against Coronavirus disease 2019 (Covid-19) lasts longer than 6 months is unclear.

Methods: A retrospective cohort study was conducted using Swedish nationwide registries. The cohort comprised 842,974 pairs (N=1,684,958), including individuals vaccinated with 2 doses of ChAdOx1 nCoV-19, mRNA-1273, or BNT162b2, and matched unvaccinated individuals. Cases of symptomatic infection and severe Covid-19 (hospitalization or 30-day mortality after confirmed infection) were collected from 12 January to 4 October 2021. 

Findings: Vaccine effectiveness of BNT162b2 against infection waned progressively from 92% (95% CI, 92-93, P<0·001) at day 15-30 to 47% (95% CI, 39-55, P<0·001) at day 121-180, and from day 211 and onwards no effectiveness could be detected (23%; 95% CI, -2-41, P=0·07). The effectiveness waned slightly slower for mRNA-1273, being estimated to 59% (95% CI, 18-79) from day 181 and onwards. In contrast, effectiveness of ChAdOx1 nCoV-19 was generally lower and waned faster, with no effectiveness detected from day 121 and onwards (-19%, 95% CI, -97-28), whereas effectiveness from heterologous ChAdOx1 nCoV-19 / mRNA was maintained from 121 days and onwards (66%; 95% CI, 41-80). Overall, vaccine effectiveness was lower and waned faster among men and older individuals. For the outcome severe Covid-19, effectiveness waned from 89% (95% CI, 82-93, P<0·001) at day 15-30 to 42% (95% CI, -35-75, P=0·21) from day 181 and onwards, with sensitivity analyses showing notable waning among men, older frail individuals, and individuals with comorbidities.

Interpretation: Vaccine effectiveness against symptomatic Covid-19 infection wanes progressively over time across all subgroups, but at different rate according to type of vaccine, and faster for men and older frail individuals. The effectiveness against severe illness seems to remain high through 9 months, although not for men, older frail individuals, and individuals with comorbidities. This strengthens the evidence-based rationale for administration of a third booster dose.

Preprint available (Oct. 25, 2021) at:

https://dx.doi.org/10.2139/ssrn.3949410

(Reuters) - AstraZeneca and Oxford University’s COVID-19 vaccine is more effective when its second dose is given three months after the first, instead of six weeks, a peer-reviewed study published in The Lancet medical journal showed on Friday. The study confirmed the Anglo-Swedish drugmaker’s findings from earlier this month that showed the vaccine had 76% efficacy against symptomatic coronavirus infection for three months after the first dose. Efficacy was found to be at 81% with the longer interval of 12 weeks between the first and second dose, compared with 55% efficacy up to the six-week gap, according to the Lancet study, which backs British and WHO recommendations for longer intervals. (bit.ly/3bmLX25) Faced with a resurgence in infections and new, highly transmissible variants of the virus, many countries are hoping to broaden immunization by giving some protection to as many people as possible with a first dose, while delaying subsequent shots.

Findings in The Lancet (Feb. 19, 2021):

http://www.thelancet-press.com/embargo/oxfordvaccineinterval.pdf 

The AstraZeneca vaccine, developed in partnership with Oxford University, is the third to announce positive trial results this month. AstraZeneca said Monday that its coronavirus vaccine reduced the risk of symptomatic Covid-19 by an average of 70.4%, according to an interim analysis of large Phase 3 trials conducted in the United Kingdom and Brazil. The results, while positive, suggest the vaccine may be less effective than two others. Earlier this month, Moderna and the Pfizer and BioNTech consortium announced their messenger RNA, or mRNA, vaccines showed 95% efficacy against Covid-19 infections in their respective clinical trials. Still, researchers at the University of Oxford, which partnered with AstraZeneca to develop the vaccine, hailed the latest data as promising. “The announcement today takes us another step closer to the time when we can use vaccines to bring an end to the devastation caused by SARS-CoV-2,” Sarah Gilbert, one of the co-developers of the vaccine, said in a statement.

The preliminary results on the AstraZeneca vaccine were based on a total of 131 Covid-19 cases in a study involving 11,363 participants. The findings were perplexing. Two full doses of the vaccine appeared to be only 62% effective at preventing disease, while a half dose, followed by a full dose, was about 90% effective. That latter analysis was conducted on a small subset of the study participants, only 2,741. A U.S.-based trial, being supported by Operation Warp Speed, is testing the two-full-dose regimen. That may soon change. AstraZeneca plans to explore adding the half dose-full dose regimen to its ongoing clinical trials in discussions with regulatory agencies, a spokesman told STAT in an email. “We see a lot of merit in this regimen and we will now start discussions with regulators into incorporating this dose combination for further clinical investigation,’’ Brendan McEvoy said. Why would less vaccine produce a better result?  “That’s a good question,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told STAT. Fauci suggested “there’s going to be a lot of hand waving” as people try to explain the results. If a final analysis, conducted after the inclusion of additional data, concludes the vaccine’s actual efficacy is around 70%, that could be a problem. “If it’s 70%, then we’ve got a dilemma,” said Fauci. “Because what are you going to do with the 70% when you’ve got two [vaccines] that are 95%? Who are you going to give a vaccine like that to?” He noted, though, that full datasets — which the Oxford researchers said they intend to publish in a scientific journal — need to be pored over before conclusions can be drawn. “We’ve got to look at the analyses, the real granular data. It’s always tough when you’re looking at a press release to figure out what’s going on,” Fauci said.

The Oxford researchers suggested the vaccine may reduce transmission of the virus, because they saw fewer asymptomatic cases in their trial. One of the challenges of controlling spread of the SARS-CoV-2 virus is that some people who become infected have no symptoms but can still transmit the virus. There were no hospitalized or severe cases of Covid-19 reported in the studies. No serious safety events related to the vaccine occurred in the studies, AstraZeneca said. Results from the U.S. trial will be delayed because that trial was paused for more than a month after one of the participants in the U.K. trial developed a rare but neurological condition, described as consistent with transverse myelitis. The Food and Drug Administration allowed the trial to resume in late October. AstraZeneca said in a release that it intends to seek emergency use authorizations in countries around the world that have a regulatory framework that allows for conditional or early approval of medical products, and will seek an emergency use listing from the World Health Organization, a pathway to rapid approval for low-income countries. The vaccine can be stored at normal refrigeration temperatures for up to six months, which will make it easier to deploy in more settings than the vaccines from Pfizer and Moderna, which must be stored at ultra-low temperatures. The Pfizer vaccine must be stored at -94 degrees Fahrenheit, while the Moderna must be stored at -4 F. Once thawed, Moderna’s vaccine can be stored at fridge temperature for a month. “The vaccine’s simple supply chain and our no-profit pledge and commitment to broad, equitable and timely access means it will be affordable and globally available,” AstraZeneca CEO Pascal Soriot said in a statement. AstraZeneca said it is on track to be able to produce 3 billion doses of its vaccine in 2021.

AstraZeneca's release (Nov. 23, 2020):

https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html