First large-scale peer-reviewed study of real-world effectiveness of COVID-19 vaccine by Israel’s Clalit Research Institute published in The New England Journal of Medicine

Thursday, February 25, 2021

Major study, conducted in collaboration with researchers from Harvard University, examined data on 600,000 vaccinated individuals in Israel, along with 600,000 matched unvaccinated controls.
Two doses of Pfizer/BioNTech vaccine reduced symptomatic COVID-19 by 94% and severe disease by 92%; Single dose reduced symptomatic COVID-19 by 57% and severe disease by 62%; Vaccine effectiveness was found to be similar across age groups; B.1.1.7 variant became dominant in Israel during the study period.

The Clalit Research Institute, in collaboration with researchers from Harvard University, analyzed one of the world’s largest integrated health record databases to examine the effectiveness of the Pfizer vaccine against COVID-19. The study provides the first large-scale peer-reviewed evaluation of the effectiveness of a COVID-19 vaccine in a nationwide mass-vaccination setting. The study was conducted in Israel, which currently leads the world in COVID-19 vaccination rates.
The results of this study validate and complement the previously reported findings of the Pfizer/BioNTech Phase-III randomized clinical trial, which focused on symptomatic infections, and which, with 21,720 vaccinated individuals, could not precisely assess vaccine effectiveness against severe disease in the fully vaccinated. The present study’s large size allows a more detailed assessment of the vaccine’s effectiveness in preventing a wider range of outcomes, across different time periods and population sub-groups.
The study took place from December 20, 2020, the launch of Israel’s national vaccination drive to February 1, 2021. It coincided with Israel’s third and largest wave of coronavirus infection and illness, during which the B.1.1.7 variant gradually became the dominant strain in the country for new infections.
Researchers reviewed data from 596,618 vaccinated individuals aged 16 and over (of whom approximately 170,000 were aged 60+). These individuals were carefully matched with 596,618 unvaccinated individuals based on an extensive set of demographic, geographic and health-related attributes associated with risk of infection, risk of severe disease, health status and health seeking behavior. Individuals were assigned to each group dynamically based on their changing vaccination status (approximately 85,000 individuals moved from the unvaccinated cohort into the vaccinated cohort during the study). Multiple sensitivity analyses were conducted to ensure that the estimated vaccine effectiveness was robust to potential biases.

The results show that in fully vaccinated individuals (7 or more days after the second dose), the risk of symptomatic COVID-19 decreased by 94% compared with the unvaccinated, while the risk of severe disease decreased by 92%. In the period immediately preceding the second dose (days 14-20 after the first dose), vaccine effectiveness was lower, but still substantial — the risk of symptomatic COVID-19 decreased by 57% in vaccinated individuals, and the risk of severe disease by 62%. While there was insufficient data to provide an estimate on the reduction in mortality in those who received two doses, data from 21-27 days after the first dose points to a substantial reduction in mortality as well.
As an observational study conducted in a mass-vaccination setting, this study was not designed to systematically assess viral transmission or asymptomatic infections. With the careful matching procedures, multiple outcomes assessed and multiple sensitivity analyses performed, the large sample size in this study also allowed the estimation of vaccine effectiveness in a number of specific subpopulations. The vaccine effectiveness for preventing symptomatic COVID-19 proved consistent across age groups, including adults aged 70+. The study also evaluated subpopulations with different numbers of comorbidities and found indications that vaccine effectiveness for preventing symptomatic COVID-19 may be slightly lower for individuals with a higher number of comorbidities, although the difference was not statistically significant.

The research was conducted by Dr. Noa Dagan, Dr. Noam Barda, Dr. Eldad Kepten, Oren Miron, Shai Perchik, Dr. Mark Katz and Prof. Ran Balicer from the Clalit Research Institute, as well as Prof. Miguel Hernán and Prof. Marc Lipsitch of the Harvard T.H. Chan School of Public Health, and Prof. Ben Reis of Boston Children’s Hospital and Harvard Medical School.

“The swift nationwide rollout of Israel’s COVID-19 vaccination campaign provided the Clalit Research Institute with a unique opportunity to assess, through its rich digital datasets, the effects of the vaccine in a real-world setting in all population sub-groups,” said Prof. Ran Balicer, senior author of the study, Director of the Clalit Research Institute and Chief Innovation Officer for Clalit. “These results show convincingly that this vaccine is highly effective against symptomatic COVID-19, one week after the second dose. These results are similar to those reported in the previously published clinical trial, despite the challenges inherent in a mass-vaccination setting.”
“The results also correlate well with recent population-level trends in Israel, which have seen a sustained decline in hospitalization and severe disease in the mostly-vaccinated older age groups, alongside a delayed decline among younger age groups for whom vaccination began several weeks later. These data, together with the anticipated impact of the ongoing vaccination campaign in Israel, where nearly half the population has already been vaccinated, have had a significant impact on government decisions to ease restrictions imposed during Israel’s recent third lockdown,” explains Prof. Balicer, who also serves as Chairman of Israel’s National Expert Advisory Team on COVID-19 response.

Prof. Miguel Hernán of the Harvard T.H. Chan School of Public Health, said, “This research is a perfect example of how randomized trials and observational healthcare databases complement each other. The original trial of the Pfizer/BioNTech vaccine provided compelling evidence of its effectiveness to prevent symptomatic infection, but the estimates for severe disease and specific age groups were too imprecise. This analysis of Clalit’s high-quality database emulates the design of the original trial, uses its findings as a benchmark, and expands upon them to confirm the vaccine’s effectiveness on severe disease and in different age groups. This combination of evidence from randomized trials and observational studies is a model for efficient medical research, something which is especially important in COVID times.”
Prof. Marc Lipsitch, Director of the Center for Communicable Disease Dynamics and Professor at the Harvard T.H. Chan School of Public Health, said, “In all studies of vaccine effectiveness, a major challenge is to ensure that those we are comparing to identify the vaccine’s effect are similar in the other characteristics that may predict whether they get infected or ill. This is especially hard in the context of a rapidly growing, age-targeted vaccine campaign. Clalit’s extraordinary database made it possible to design a study that addressed these challenges in a way that provides tremendous confidence in the inferences that come out of the study.”
Prof. Ben Reis, Director of the Predictive Medicine Group at Boston Children’s Hospital and Harvard Medical School, said, “Israel’s impressive vaccination campaign, together with Clalit’s unique integrated data sources, presented a rare opportunity to study the effects of the vaccine in a real-world mass-vaccination setting.” He continued, “The global scientific cavalry charge that enabled the development of vaccines in record time is now continuing with international collaborations focused on evaluating vaccine effectiveness. The virus doesn’t recognize borders, neither should the scientists hoping to fight it. This is how science should be done.”

See the publication here

About Clalit and Clalit Research Institute
Clalit is the world’s longest-running integrated payer/provider health organization, and among the world’s largest. For over 100 years, Clalit has been at the forefront of medical care and health innovation. Clalit provides primary, secondary and inpatient care to more than 4.7 million members – over 52% of Israel’s population. Clalit’s 14 hospitals and over 1,600 clinics and facilities provide integrated care to patients and their families across the country. Clalit’s comprehensive electronic medical records include over two decades of clinical and administrative information, providing an unprecedented source of Big Data for research and innovation for the benefit of the Clalit members. The Clalit Research Institute utilizes this rich data to drive real-world outcome research and promote translational studies, yielding data-driven policy initiatives and innovative predictive care models. The tools and insights gained by the Clalit Research Institute’s work are implemented in the daily practice of the frontline healthcare workers of Clalit and in the digital health framework that Clalit provides to its members and patients, to improve care access and effectiveness for people of all backgrounds.

About Harvard T.H. Chan School of Public Health
Harvard T.H. Chan School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people’s lives—not only making scientific breakthroughs, but also working to change individual behaviors, public policies, and health care practices. Each year, more than 400 faculty members at Harvard Chan School teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognized as America’s oldest professional training program in public health.

About Boston Children’s Hospital
Boston Children’s Hospital is ranked the #1 children’s hospital in the nation by U.S. News & World Report and is the primary pediatric teaching affiliate of Harvard Medical School. Home to the world’s largest research enterprise based at a pediatric medical center, its discoveries have benefited both children and adults since 1869. Today, 3,000 researchers and scientific staff, including 9 members of the National Academy of Sciences, 23 members of the National Academy of Medicine and 12 Howard Hughes Medical Investigators comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s is now a 415-bed comprehensive center for pediatric and adolescent health care.

Press Contact:
Ms. Maya Kotler
Director of Media Relations, Clalit Research Institute