Israel
Israeli Study Shows How COVID-19 Immunity Wanes over Time
Posted on by Dr. Francis Collins
The winter holidays are approaching, and among the many things to be grateful for this year is that nearly 200 million Americans are fully vaccinated for COVID-19. That will make it safer to spend time with friends and family, though everyone should remain vigilant just to be on the safe side. Though relatively uncommon, breakthrough infections are possible. That’s why the Centers for Disease Control and Prevention (CDC) recommends booster shots for several at-risk groups, including folks 65 years and older, those with underlying medical conditions, and people whose occupations place them at high risk of exposure.
One of the main studies providing the evidence for CDC’s recommendation was recently published in the New England Journal of Medicine [1]. It found that vaccine-induced immunity, while still quite protective against infection and severe illness from COVID-19, can wane after several months.
The study is yet another highly informative report from Israel, where public health officials launched a particularly vigorous national vaccination campaign in December 2020. More than half of adult Israelis received two doses of the Pfizer vaccine within the first three months of the campaign. By May 2021, Israel had extremely small numbers of confirmed COVID-19 cases—just a few dozen per day.
But the numbers crept back up in June 2021. The rise also included a substantial number of breakthrough infections in vaccinated individuals. The vast majority of those cases in June—98 percent—were caused by the emerging Delta variant.
Researchers led by Yair Goldberg, Technion-Israel Institute of Technology, Haifa, wondered whether this resurgence of COVID-19 could be fully explained by the rise of the more infectious Delta variant. Or, they wondered, did the waning of immunity over time also play a role?
To find out, the researchers looked to over 4.7 million fully vaccinated Israeli adults, more than 13,000 of whom had breakthrough infections from July 11 to 31, 2021 with SARS-CoV-2. The researchers looked for an association between the rate of confirmed infections and the time that had passed since vaccination. Without any significant waning of immunity, one shouldn’t see any difference in infection rates among people who were fully vaccinated at the earliest opportunity versus those vaccinated later.
The results were clear: the rate of confirmed COVID-19 infection revealed a slow but steady waning of immunity over time. Among individuals 60 years or older who were fully vaccinated last January, the number of confirmed breakthrough infections was 3.3 per 1,000 people during the three weeks of the study. Those who were vaccinated in February and March had lower infection rates of 2.2 per 1,000 and 1.7 per 1,000, respectively. The data revealed a similar pattern in those aged 40 to 59 and those aged 16 to 39.
An important question is whether these breakthrough infections were serious enough to require hospitalization. While such cases were much less common, more than 400 of those with confirmed COVID-19 breakthroughs went on to develop severe illness. And, again, the data show a similar pattern of waning immunity. The rate of severe COVID-19 among adults 60 years of age or older who were fully vaccinated in January was 0.34 cases per 1,000 persons. The rate of severe illness dropped to 0.26 cases per 1,000 among those vaccinated in February and 0.15 cases per 1,000 for those vaccinated in March. The researchers report that the number of severe COVID-19 cases among the younger fully vaccinated groups were too small to draw any conclusions.
While the Delta variant surely has played a role in the resurgence of COVID-19 in recent months, these findings suggest that waning immunity also is an important factor. Understanding these dynamics is essential for making critical policy decisions. In fact, these data were a key factor in the decision by the Israeli Ministry of Health in July 2021 to approve administration of COVID-19 booster shots for individuals who’d been vaccinated at least 5 months before.
Back in the U.S., if you were among those who got your vaccine on the early side—good for you. If it’s been more than six months since your original shots, and if you are in one of the risk groups, you should consider a COVID-19 booster shot to remain optimally protected in the months ahead. I’ll be getting my Moderna booster this week. While you’re at it, consider getting your annual flu shot taken care of, too. The CDC guidelines state that it’s perfectly OK to get your COVID-19 and flu shots at the same time.
Reference:
[1] Waning immunity after the BNT162b2 vaccine in Israel. Goldberg Y, Mandel M, Bar-On YM, Bodenheimer O, Freedman L, Haas EJ, Milo R, Alroy-Preis S, Ash N, Huppert A. N Engl J Med. 2021 Oct 27.
Links:
COVID-19 Research (NIH)
COVID-19 Vaccine Booster Shots (Centers for Disease Control and Prevention)
Frequently Asked Influenza (Flu) Questions: 2021-2022 Season (CDC)
Breakthrough Infections Occur in Those with Lower Antibody Levels, Israeli Study Shows
Posted on by Dr. Francis Collins
To see how COVID-19 vaccines are working in the real world, Israel has provided particularly compelling data. The fact that Israel is relatively small, keeps comprehensive medical records, and has a high vaccination rate with a single vaccine (Pfizer) has contributed to its robust data collection. Now, a new Israeli study offers some insight into those relatively uncommon breakthrough infections. It confirms that breakthrough cases, as might be expected, arise most often in individuals with lower levels of neutralizing antibodies.
The findings reported in The New England Journal of Medicine focused on nearly 1,500 of about 11,500 fully vaccinated health care workers at Sheba Medical Center, Ramat Gan, Israel [1]. All had received two doses of the Pfizer mRNA vaccine. But, from December 19, 2020 to April 28, 2021, they were tested for a breakthrough infection due to a known exposure to someone with COVID-19 or possible symptoms of the disease.
Just 39 confirmed breakthrough cases were found, indicating a breakthrough infection rate of just 0.4 percent. That’s consistent with rates reported in previous studies. Most in the Israeli study who tested positive for COVID-19 had mild or no symptoms and none required hospitalization.
In the new study, researchers led by Gili Regev-Yochay at Sheba Medical Center’s Infection Control and Prevention Unit, characterized as many breakthrough infections as possible among the health care workers. Almost half of the infections involved members of the hospital nursing staff. But breakthrough cases also were found in hospital administration, maintenance workers, doctors, and other health professionals.
The average age of someone with a breakthrough infection was 42, and it’s notable that only one person was known to have a weakened immune system. The most common symptoms were respiratory congestion, muscle aches (myalgia), and loss of smell or taste. Most didn’t develop a fever. At six weeks after diagnosis, 19 percent reported having symptoms of Long COVID syndrome, including prolonged loss of smell, persistent cough, weakness, and fatigue. About a quarter stayed home from work for longer than the required 10 days, and one had yet to return to work at six weeks.
For 22 of the 39 people with a breakthrough infection, the researchers had results of neutralizing antibody tests from the week leading up to their positive COVID-19 test result. To look for patterns in the antibody data, they matched those individuals to 104 uninfected people for whom they also had antibody test results. These data showed that those with a breakthrough infection had consistently lower levels of neutralizing antibodies circulating in their bloodstream to SARS-CoV-2, the coronavirus that causes COVID-19. In general, higher levels of neutralizing antibodies are associated with greater protection and lower infectivity—though other aspects of the immune system (memory B cells and cell-mediated immunity) also contribute.
Importantly, in all cases for which there were relevant data, the source of the breakthrough infection was thought to be an unvaccinated person. In fact, more than half of those who developed a breakthrough infection appeared to have become infected from an unvaccinated member of their own household.
Other cases were suspected to arise from exposure to an unvaccinated coworker or patient. Contact tracing found no evidence that any of the 39 health care workers with a breakthrough infection passed it on to anyone else.
The findings add to evidence that full vaccination and associated immunity offer good protection against SARS-CoV-2 infection and severe illness. Understanding how SARS-CoV-2 immunity changes over time is key for charting the course of this pandemic and making important decisions about COVID-19 vaccine boosters.
Many questions remain. For instance, it’s not clear from the study whether lower neutralizing antibodies in those with breakthrough cases reflect waning immunity or, for reasons we don’t yet understand, those individuals may have had a more limited immune response to the vaccine. Also, this study was conducted before the Delta variant became dominant in Israel (and now in the whole world).
Overall, these findings provide more reassurance that these vaccines are extremely effective. Breakthrough infections, while they can and do occur, are a relatively uncommon event. Here in the U.S., the Centers for Disease Control and Prevention (CDC) has recently estimated that infection is six times less likely for vaccinated than unvaccinated persons [2]. That those with immunity tend to have mild or no symptoms if they do develop a breakthrough case, however, is a reminder that these cases could easily be missed, and they could put vulnerable populations at greater risk. It’s yet another reason for all those who can to get themselves vaccinated as soon as possible or consider a booster shot when they become eligible.
References:
[1] Covid-19 breakthrough infections in vaccinated health care workers. Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C, Mandelboim M, Levin EG, Rubin C, Indenbaum V, Tal I, Zavitan M, Zuckerman N, Bar-Chaim A, Kreiss Y, Regev-Yochay G. N Engl J Med. 2021 Oct 14;385(16):1474-1484.
[2] Rates of COVID-19 cases and deaths by vaccination status, COVID Data Tracker, Centers for Disease and Prevention. Accessed October 25, 2021.
Links:
COVID-19 Research (NIH)
Sheba Medical Center (Ramat Gan, Israel)
The Latest on COVID-19 Boosters
Posted on by Dr. Francis Collins
More than 180 million Americans, including more than 80 percent of people over age 65, are fully vaccinated against the SARS-CoV-2 virus responsible for COVID-19. There’s no question that full vaccination is the best way to protect yourself against this devastating virus and reduce your chances of developing severe or long-lasting illness if you do get sick. But, to stay ahead of this terrible virus, important questions do remain. A big one right now is: How soon will booster shots be needed and for whom?
The answers to this question will continue to evolve as more high-quality data become available. But here’s what we know right now for the Pfizer-BioNTech booster. Late last week, Dr. Rochelle Walensky, the Director of the Centers for Disease Control and Prevention (CDC), recommended that:
- Those 65 years and older and residents in long-term care settings should receive a booster shot at least 6 months after being fully vaccinated with the Pfizer-BioNTech vaccine,
- People aged 50–64 years with underlying medical conditions should receive a booster shot at least 6 months after being fully vaccinated with the Pfizer-BioNTech vaccine,
- Individuals aged 18–49 years with underlying medical conditions may receive a booster shot at least 6 months after getting fully vaccinated with their Pfizer-BioNTech vaccine, based on their individual benefits and risks.
- Frontline workers who received the Pfizer-BioNTech vaccine may receive a booster. This group includes anyone age 18 through 64 whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of COVID-19. [1]
Taken together, these CDC recommendations are in line with those issued two days earlier by the Food and Drug Administration (FDA) [2].
Some of the most-compelling data that was under review came from an Israeli study, published recently in the New England Journal of Medicine, that explored the benefit of booster shots for older people [3]. Israel, with a population of around 9 million, has a national health system and one of the world’s highest COVID-19 vaccination rates. That country’s vaccination campaign, based solely on Pfizer-BioNTech, was organized early in 2021, and so its experience is about three months ahead of ours here in the U.S. These features, plus some of the world’s largest integrated health record databases, have made Israel an important source of early data on how the Pfizer-BioNTech mRNA vaccine can be expected to work in the real world over time.
Earlier this year, Israeli public health officials noted evidence for an increased number of breakthrough infections, some of which were severe. So, at the end of July 2021, Israel approved the administration of third doses, or “boosters,” of the Pfizer-BioNTech vaccine for people ages 60 and up who had received their second dose at least five months before.
To find out how well these booster shots worked to bolster immune protection against COVID-19, researchers looked to more than 1.1 million fully vaccinated people who were at least 60 years old. They compared the rate of confirmed COVID-19 infection and severe illness from the end of July to the end of August among people who’d received a booster at least 12 days earlier with those who hadn’t gotten boosters.
Nearly 13,500 older individuals who’d been fully vaccinated before March 2021, got a breakthrough infection during the two months of study. Importantly, the rate of confirmed infection in the group that got boosters was 10 times lower on average than in the group that didn’t get boosters. The data on severe illness looked even better. Of course, there could be other factors at play that weren’t accounted for in the study, but the findings certainly suggest that a third Pfizer shot is safe and effective for older people.
Though the Israeli studies on booster shots are a little ahead of the international pack, we are starting to see results from the research underway in the U.S. Last week, for example, Johnson & Johnson announced new data in support of boosters to improve and extend immune protection in those who received its single-dose COVID-19 vaccine [4]. For people who received the Moderna mRNA vaccine, the company has already submitted its data to the FDA for booster authorization. A decision is expected soon.
As the critical evidence on boosters continues to emerge, the most important way to avoid another winter surge of COVID-19 is to follow all public health recommendations. Most importantly, that includes getting fully vaccinated if you haven’t already, and encouraging others around you to do the same. If you’re currently eligible for a booster shot, they are available at 80,000 locations across the nation, and can help you stay healthy and well for the coming holiday season.
For others eager to do everything possible to protect themselves, their families, and their communities against this terrible virus—but who are not yet eligible for a booster—sit tight for now. The data on booster shots are still coming in for folks like me who were immunized with the Moderna or Johnson & Johnson vaccines. It’s likely that the FDA and CDC will widen their recommendations in the coming weeks.
In the meantime, the Delta variant is still out there and circulating. That makes it critical to maintain vigilance. Wear a mask in indoor spaces, keep a physical distance from others, and remember to wash your hands frequently. We are all really tired of COVID-19, but patience is still required as we learn more about how best to stay ahead of this virus.
References:
[1] CDC statement on ACIP booster recommendations. Centers for Disease Control and Prevention news release. September 24, 2021
[2] FDA authorizes booster dose of Pfizer-BioNTech COVID-19 vaccine for certain populations. Food and Drug Administration news release. September 22, 2021
[3] Protection of BNT162b2 vaccine booster against Covid-19 in Israel. Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Freedman L, Kalkstein N, Mizrahi B, Alroy-Preis S, Ash N, Milo R, Huppert A. N Engl J Med. 2021 Sep 15.
[4] Johnson & Johnson announces real-world evidence and Phase 3 data confirming strong and long-lasting protection of single-shot COVID-19 vaccine in the U.S. Johnson & Johnson. September 21, 2021.
Links:
COVID-19 Research (NIH)
A Real-World Look at COVID-19 Vaccines Versus New Variants
Posted on by Dr. Francis Collins
Clinical trials have shown the COVID-19 vaccines now being administered around the country are highly effective in protecting fully vaccinated individuals from the coronavirus SARS-CoV-2. But will they continue to offer sufficient protection as the frequency of more transmissible and, in some cases, deadly emerging variants rise?
More study and time is needed to fully answer this question. But new data from Israel offers an early look at how the Pfizer/BioNTech vaccine is holding up in the real world against coronavirus “variants of concern,” including the B.1.1.7 “U.K. variant” and the B.1.351 “South African variant.” And, while there is some evidence of breakthrough infections, the findings overall are encouraging.
Israel was an obvious place to look for answers to breakthrough infections. By last March, more than 80 percent of the country’s vaccine-eligible population had received at least one dose of the Pfizer/BioNTech vaccine. An earlier study in Israel showed that the vaccine offered 94 percent to 96 percent protection against infection across age groups, comparable to the results of clinical trials. But it didn’t dig into any important differences in infection rates with newly emerging variants, post-vaccination.
To dig a little deeper into this possibility, a team led by Adi Stern, Tel Aviv University, and Shay Ben-Shachar, Clalit Research Institute, Tel Aviv, looked for evidence of breakthrough infections in several hundred people who’d had at least one dose of the Pfizer/BioNTech vaccine [1]. The idea was, if this vaccine were less effective in protecting against new variants of concern, the proportion of infections caused by them should be higher in vaccinated compared to unvaccinated individuals.
During the study, reported as a pre-print in MedRxiv, it became clear that B.1.1.7 was the predominant SARS-CoV-2 variant in Israel, with its frequency increasing over time. By comparison, the B.1.351 “South African” variant was rare, accounting for less than 1 percent of cases sampled in the study. No other variants of concern, as defined by the World Health Organization, were detected.
In total, the researchers sequenced SARS-CoV-2 from more than 800 samples, including vaccinated individuals and matched unvaccinated individuals with similar characteristics including age, sex, and geographic location. They identified nearly 250 instances in which an individual became infected with SARS-CoV-2 after receiving their first vaccine dose, meaning that they were only partially protected. Almost 150 got infected sometime after receiving the second dose.
Interestingly, the evidence showed that these breakthrough infections with the B.1.1.7 variant occurred slightly more often in people after the first vaccine dose compared to unvaccinated people. No evidence was found for increased breakthrough rates of B.1.1.7 a week or more after the second dose. In contrast, after the second vaccine dose, infection with the B.1.351 became slightly more frequent. The findings show that people remain susceptible to B.1.1.7 following a single dose of vaccine. They also suggest that the two-dose vaccine may be slightly less effective against B.1.351 compared to the original or B.1.1.7 variants.
It’s important to note, however, that the researchers only observed 11 infections with the B.1.351 variant—eight of them in individuals vaccinated with two doses. Interestingly, all eight tested positive seven to 13 days after receiving their second dose. No one in the study tested positive for this variant two weeks or more after the second dose.
Many questions remain, including whether the vaccines reduced the duration and/or severity of infections. Nevertheless, the findings are a reminder that—while these vaccines offer remarkable protection—they are not foolproof. Breakthrough infections can and do occur.
In fact, in a recent report in the New England Journal of Medicine, NIH-supported researchers detailed the experiences of two fully vaccinated individuals in New York who tested positive for COVID-19 [2]. Though both recovered quickly at home, genomic data in those cases revealed multiple mutations in both viral samples, including a variant first identified in South Africa and Brazil, and another, which has been spreading in New York since November.
These findings in Israel and the United States also highlight the importance of tracking coronavirus variants and making sure that all eligible individuals get fully vaccinated as soon as they have the opportunity. They show that COVID-19 testing will continue to play an important role, even in those who’ve already been vaccinated. This is even more important now as new variants continue to rise in frequency.
Just over 100 million Americans aged 18 and older—about 40 percent of adults—are now fully vaccinated [3]. However, we need to get that number much higher. If you or a loved one haven’t yet been vaccinated, please consider doing so. It will help to save lives and bring this pandemic to an end.
References:
[1] Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2 mRNA vaccinated individuals. Kustin T et al. medRxiv. April 16, 2021.
[2] Vaccine breakthrough infections with SARS-CoV-2 variants. Hacisuleyman E, Hale C, Saito Y, Blachere NE, Bergh M, Conlon EG, Schaefer-Babajew DJ, DaSilva J, Muecksch F, Gaebler C, Lifton R, Nussenzweig MC, Hatziioannou T, Bieniasz PD, Darnell RB. N Engl J Med. 2021 Apr 21.
[3] COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention.
Links:
COVID-19 Research (NIH)
Stern Lab (Tel Aviv University, Israel)
Ben-Shachar Lab (Clalit Research Institute, Tel Aviv, Israel)
NIH Support: National Institute of Allergy and Infectious Diseases
Israeli Study Offers First Real-World Glimpse of COVID-19 Vaccines in Action
Posted on by Dr. Francis Collins
There are many reasons to be excited about the three COVID-19 vaccines that are now getting into arms across the United States. At the top of the list is their extremely high level of safety and protection against SARS-CoV-2, the coronavirus that causes COVID-19. Of course, those data come from clinical trials that were rigorously conducted under optimal research conditions. One might wonder how well those impressive clinical trial results will translate to the real world.
A new study published in the New England Journal of Medicine [1] offers an early answer for the Pfizer/BioNTech vaccine. The Pfizer product is an mRNA vaccine that was found in a large clinical trial to be up to 95 percent effective in preventing COVID-19, leading to its Emergency Use Authorization last December.
The new data, which come from Israel, are really encouraging. Based on a detailed analysis of nearly 600,000 people vaccinated in that nation, a research team led by Ran Balicer, The Clalit Research Institute, Tel Aviv, found that the risk of symptomatic COVID-19 infection dropped by 94 percent a week after individuals had received both doses of the Pfizer vaccine. That’s essentially the same very high level of protection that was seen in the data gathered in the earlier U.S. clinical trial.
The study also found that just a single shot of the two-dose vaccine led to a 57 percent drop in the incidence of symptomatic COVID-19 infections and a 62 percent decline in the risk of severe illness after two to three weeks. Note, however, that the protection clearly got better after folks received the second dose. While it’s too soon to say how many lives were saved in Israel thanks to full vaccination, the early data not surprisingly suggest a substantial reduction in mortality.
Israel, which is about as large as New Jersey with a population of around 9 million, currently has the world’s highest COVID-19 vaccination rate. In addition to its relatively small size, Israel also has a national health system and one of the world’s largest integrated health record databases, making it a natural choice to see how well one of the new vaccines was working in the real world.
The study took place from December 20, 2020, the start of Israel’s first vaccination drive, through February 1, 2021. This also coincided with Israel’s third and largest wave of COVID-19 infections and illness. During this same period, the B.1.1.7 variant, which was first detected in the United Kingdom, gradually became Israel’s dominant strain. That’s notable because the U.K. variant spreads from person-to-person more readily and may be associated with an increased risk of death compared with other variants [2].
Balicer and his colleagues reviewed data on 596,618 fully vaccinated individuals, ages 16 and older. A little less than one third—about 170,000—of the people studied were over age 60. To see how well the vaccine worked, the researchers carefully matched each of the vaccinated individuals in the study to an unvaccinated person with similar demographics as well as risks of infection, severe illness, and other important health attributes.
The results showed that the vaccine works remarkably well. In fact, the researchers determined that the Pfizer/BioNTech vaccine is similarly effective—94 percent to 96 percent—across adults in different age groups. It also appears that the vaccine works about equally well for individuals age 70 and older as it does for younger people.
So far, more than 92 million total vaccine doses have been administered in the U.S. With the Janssen COVID-19 vaccine (also called the Johnson & Johnson vaccine) now coming online, that number will rise even faster. For those of you who haven’t had the opportunity just yet, these latest findings should come as added encouragement to roll up your sleeve for any one of the authorized vaccines as soon as your invitation arrives.
References:
[1] BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, Hernán MA, Lipsitch M, Reis B, Balicer RD. N Engl J Med. 2021 Feb 24.
[2] Emerging SARS-CoV-2 Variants. Centers for Disease Control and Prevention.
Links:
COVID-19 Research (NIH)
Clalit Research Institute (Tel Aviv, Israel)
Ran Balicer (Clalit Research Institute)
