The signal we could not ignore
How large-scale health data revealed the unusual dynamics of immunity obtained through mRNA vaccines
In early 2021, Israel became one of the first countries in the world to deploy a nationwide COVID-19 vaccination campaign using the Pfizer-BioNTech mRNA vaccine.
After an initial period of lockdowns and overflowing hospitals, the vaccination campaign quickly reduced the rate of new COVID-19 cases and severe disease across the country. Israel quickly became a global model for large-scale vaccination. Restrictions were lifted. Daily life began returning to normal. There was genuine optimism that the pandemic might be ending.
At the Leumit Research Institute, where we continuously analyze nationwide longitudinal electronic health records, we began tracking the immune response to SARS-CoV-2 in the population.
The early antibody response following mRNA vaccination was remarkably strong.
In individuals vaccinated with two doses of the Pfizer-BioNTech vaccine, antibody titers often reached levels around 10,000 AU/mL shortly after vaccination, substantially higher than the antibody levels typically observed after natural SARS-CoV-2 infection, which were usually closer to 1,000 AU/mL.
But when we began examining how antibody levels changed over time, an unexpected pattern emerged.
The immune response induced by vaccination was not merely declining. It was declining very rapidly.
Using large-scale longitudinal serologic data from thousands of individuals across Israel, we observed that antibody titers following vaccination decreased by approximately 40% every month. In contrast, antibody levels following natural infection declined much more slowly, by only around 4% per month.
The difference was striking.
Although antibody levels following vaccination were initially higher than those observed after natural infection, the decline was so steep that within a few months they fell below those observed following infection.
The graphs below from our original publication illustrate this phenomenon.
Following vaccination (top), antibody titers began at very high levels but rapidly declined over time. Following natural infection (bottom), antibody levels were lower initially, but remained comparatively stable over many months. Importantly, the vertical scale in these graphs is logarithmic, meaning that each vertical step represents a tenfold decrease in antibody levels.
At the time, these findings were uncomfortable.
The immunologic dynamics suggested that although the vaccines initially appeared highly effective at reducing severe disease, the protection they conferred against infection might not remain stable for long.
Based on the observed rate of antibody decay, we became concerned that within several months, vaccine-induced protection against infection would substantially weaken, leaving vaccinated individuals increasingly susceptible to breakthrough infections.
And indeed, several months later, breakthrough infections began rising sharply in Israel during the emergence of the so-called Delta wave in the summer of 2021.
At the time, the dominant explanation was that the Delta variant had evolved mutations that enabled it to evade vaccine-induced immunity, raising concerns that protection against infection might require updated vaccines specifically adapted to the new variant.
But when we examined nationwide health data, another signal clearly emerged: the risk of infection was strongly associated with the time elapsed since vaccination.
Individuals vaccinated earlier were substantially more likely to develop breakthrough infections.
We analyzed RT-PCR results from more than 83,000 adults who had received two vaccine doses. After adjusting for demographic factors and comorbidities, the risk of infection increased progressively with time since vaccination. Individuals vaccinated more than six months earlier had nearly a threefold increased risk of infection compared with recently vaccinated individuals.
Importantly, this pattern was observed across all age groups.
At the time, this remained a controversial conclusion.
The vaccines had initially been viewed as providing relatively durable protection against infection, and the idea that immunity might substantially wane within months was uncomfortable both scientifically and politically.
Nevertheless, the data were difficult to ignore.
We rapidly disseminated these findings as a preprint, and the evidence regarding waning immunity contributed to the decision by the Israeli COVID-19 response task force to launch a nationwide booster vaccination campaign, initially targeting elderly and vulnerable individuals.
The effect of this decision was substantial.
Individuals who received the booster dose experienced a marked reduction in breakthrough infections and severe disease. The booster campaign was subsequently expanded to the general population in Israel, and similar policies were later adopted internationally.
Our study was later published in the British Medical Journal (BMJ).
This experience taught an important lesson about science and public health.
Scientific evidence is not static, and science should never become dogmatic.
While early clinical trials provide essential answers, large-scale real-world epidemiology remains indispensable. Population-level health data have the unique ability to reveal biological dynamics that are difficult to detect in controlled trials, especially when trial reports are based on limited follow-up.
We pragmatically followed vaccination effects at the population level and concluded that although mRNA vaccines substantially reduced severe disease and mortality among elderly and vulnerable individuals, they also had important limitations, including rapidly waning protection against infection among vaccinated individuals.
Recognizing these limitations early was essential for adapting public-health policy to a changing reality.
Good science requires the willingness to follow the data without preconceived conclusions, and to report findings honestly, even when the signal is uncomfortable.
References
Large-Scale Study of Antibody Titer Decay following BNT162b2 mRNA Vaccine or SARS-CoV-2 Infection.
Israel A, Shenhar Y, Green I, Merzon E, Golan-Cohen A, Schäffer AA, Ruppin E, Vinker S, Magen E.
Vaccines (Basel). 2021 Dec 31;10(1):64.
doi:10.3390/vaccines10010064.Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection in a large cohort. medRxiv. Posted August 5, 2021.
Israel A, Merzon E, Schäffer AA, Shenhar Y, Green I, Golan-Cohen A, Ruppin E, Magen E, Vinker S.
doi:https://doi.org/10.1101/2021.08.03.21261496Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection: test negative design study.
Israel A, Merzon E, Schäffer AA, Shenhar Y, Green I, Golan-Cohen A, Ruppin E, Magen E, Vinker S.
BMJ. 2021 Nov 24;375.
doi:10.1136/bmj-2021-067873.