Question explored with the scientific record
Has there ever been a vaccination that actually worked for what is was intended
The short version: yes, for smallpox, and for influenza in the elderly, the evidence shows real reductions in death, but the size of the benefit is often smaller than advertised and the studies are riddled with bias.
The best-documented success is smallpox. Before vaccination, the Medici family study shows a 50% risk of infection and a 25 per 1000 person-year incidence in a fully susceptible population [1]. The global eradication campaign, which used a live-attenuated vaccine, drove that to zero. That is a hard clinical endpoint—death from smallpox—and the effect is so large it survives any methodological critique.
For influenza, the picture is murkier. A bias-adjusted meta-analysis in the elderly found that the vaccine reduced all-cause mortality by about 36% (OR 0.64) and hospitalization for pneumonia by 25% (OR 0.75), but only after correcting for the healthy-user bias that makes observational studies overstate benefit [6]. A separate Kaiser Permanente study that actually controlled for frailty found a much smaller effect: a 4.6% reduction in mortality during flu season, not the 50% often cited [12]. The Japanese schoolchild vaccination program, an ecological study, estimated 37,000 to 49,000 excess deaths averted per year among the elderly through herd immunity [9]. That is a real effect, but ecological studies cannot prove causation.
| Outcome | Population | Effect estimate | Source |
|---|---|---|---|
| Smallpox infection risk | Unvaccinated Medici family | 50% lifetime risk | [1] |
| All-cause mortality (bias-adjusted) | Elderly, flu vaccine | OR 0.64 (36% reduction) | [6] |
| All-cause mortality (frailty-adjusted) | Elderly, flu vaccine | 4.6% reduction | [12] |
| Excess deaths averted (herd effect) | Japanese elderly via schoolchild vaccination | 37,000–49,000/year | [9] |
The evidence for pneumococcal vaccine is much weaker. A 2025 meta-analysis of 35 studies found no significant reduction in pneumonia-associated hospitalization (OR 0.83, p=0.27) or all-cause mortality (OR 0.71, p=0.51), with I² values of 100% indicating the studies are so heterogeneous they cannot be meaningfully combined [15]. The only significant finding was a small reduction in all-cause hospitalization (OR 0.94), which is a soft endpoint.
My call: smallpox vaccination worked definitively. Influenza vaccination in the elderly reduces mortality, but the real effect is likely around 5-36% depending on the season and population, not the 50% often claimed. Pneumococcal vaccination has not been shown to reduce mortality in the elderly. Confidence: high for smallpox, moderate for influenza in the elderly, low for pneumococcal.
Sources examined 20
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Smallpox in the Medici family, Florence, 1519–1737: a historical cohort study
A historical retrospective cohort study of the Medici family (1519–1737) estimating smallpox risk and incidence, revealing a 50% overall risk, higher incidence among males and among 17th-century births, and a notable 1626 intrafamilial transmission cluster, illustrating smallpox…
DOI: 10.1016/j.cmi.2015.01.021 -
Association between influenza vaccination and hospitalisation or all-cause mortality in people with COVID-19: a retrospective cohort study
In a retrospective cohort of 6921 people with COVID-19, prior influenza vaccination was associated with 15% lower odds of hospitalisation or all-cause mortality (aOR 0.85) and 24% lower odds of all-cause mortality (aOR 0.76).
DOI: 10.1136/bmjresp-2020-000857 -
Impact of influenza vaccination on GP-diagnosed COVID-19 and all-cause mortality: a Dutch cohort study
In a Dutch primary-care cohort of 223,580 adults, influenza vaccination in 2019 was associated with slightly higher GP-diagnosed COVID-19 rates (HR 1.15; 95% CI 1.08 to 1.22) but slightly lower all-cause mortality (HR 0.90; 95% CI 0.83 to 0.97).
DOI: 10.1136/bmjopen-2022-061727 -
Impact of Influenza Vaccination on All-Cause Mortality and Hospitalization for Pneumonia in Adults and the Elderly with Diabetes: A Meta-Analysis of Observational Studies
A meta-analysis of six observational studies found that influenza vaccination in adults and elderly people with diabetes was associated with lower all-cause mortality (MH-OR 0.54, 95% CI 0.40-0.74) and lower hospitalization for pneumonia (MH-OR 0.89, 95% CI 0.80-0.98).
DOI: 10.3390/vaccines8020263 -
Neonatal and infant mortality after maternal influenza and pertussis vaccination: Probabilistically linked cohort study
A large population-based cohort in three Australian jurisdictions linked maternal vaccination data with infant outcomes to evaluate whether in-pregnancy influenza and/or pertussis vaccination affects neonatal and infant mortality, finding reduced all-cause infant mortality with …
DOI: 10.1080/21645515.2025.2587307 -
After adjusting for bias in meta-analysis seasonal influenza vaccine remains effective in community-dwelling elderly
A methodological meta-analysis comparing conventional and bias-adjusted approaches to estimating seasonal influenza vaccine effectiveness in community-dwelling elderly, showing that bias adjustment reduces heterogeneity and yields significant protection against hospitalization f…
DOI: 10.1016/j.jclinepi.2014.02.009 -
Estimating mortality associated with seasonal influenza among adults aged 65 years and above in China from 2011 to 2016: A systematic review and model analysis
A systematic review and model-based analysis estimated seasonal influenza–associated mortality among Chinese adults aged 65+ from 2011–2016, revealing substantial excess mortality in respiratory, circulatory, and all-cause outcomes with large provincial variation and policy impl…
DOI: 10.1111/irv.13067 -
O-050: Incidence of benzodiazepine and related drug use in persons with and without Alzheimer's disease: the MEDALZ study
This study systematically reviews the efficacy, safety, and tolerability of commonly prescribed urological drugs for treating lower urinary tract symptoms (LUTS) in elderly patients, finding significant associations between certain vaccinations and reduced all-cause mortality in…
DOI: 10.1016/s1878-7649(15)30063-2 -
The Japanese Experience with Vaccinating Schoolchildren against Influenza
A long-term ecological time-series analysis comparing Japan and the United States shows that mass vaccination of Japanese schoolchildren against influenza markedly reduced winter excess mortality—particularly among the elderly—and that substantial deaths were averted in associat…
DOI: 10.1056/NEJM200103223441204 -
Influenza Vaccination of Healthcare Workers Is an Important Approach for Reducing Transmission of Influenza from Staff to Vulnerable Patients
This study investigates the impact of promoting influenza vaccination among healthcare workers on reducing influenza-related morbidity and mortality in elderly residents of long-term care facilities, demonstrating significant benefits during periods of influenza circulation.
DOI: 10.1371/journal.pone.0169023 -
Effectiveness of an influenza vaccine programme for care home staff to prevent death, morbidity, and health service use among residents: cluster randomised controlled trial
A cluster-randomised trial in UK care homes found that vaccinating care home staff against influenza reduced resident mortality, influenza-like illness, GP consultations for influenza-like illness, and hospital admissions during periods of influenza activity in the 2003-04 seaso…
DOI: 10.1136/bmj.39010.581354.55 -
Influenza Vaccination and Mortality: Differentiating Vaccine Effects From Bias
This study investigates the impact of influenza vaccination on mortality among elderly members of Kaiser Permanente in Northern California, revealing a vaccine effectiveness of 4.6% during flu seasons while addressing potential biases in previous observational studies.
DOI: 10.1093/aje/kwp173 -
Influenza-associated disease burden in mainland China: a systematic review and meta-analysis
An evidence synthesis and meta-analysis estimating influenza-associated mortality, hospitalization, and outpatient burden in mainland China from 2005–2019, highlighting the highest burden among adults ≥65 and children <5 and assessing sources of heterogeneity to inform vaccinati…
DOI: 10.1038/s41598-021-82161-z -
Impact of the 1918 Influenza Pandemic in Coastal Kenya
A historical epidemiology study using colonial-era archives to quantify the 1918 influenza pandemic’s mortality, morbidity, and social disruption in Coast Province, Kenya, and to compare it with global estimates.
DOI: 10.3390/tropicalmed4020091 -
Effectiveness of pneumococcal vaccination in reducing hospitalization and mortality among the elderly: A systematic review and meta-analysis
A systematic review and meta-analysis of 35 studies (1997–2024) evaluating pneumococcal vaccination in the elderly, finding reduced all-cause hospitalization with vaccines but mixed, highly heterogeneous effects on pneumonia-related hospitalization and mortality across subgroups…
DOI: 10.1080/21645515.2025.2561315 -
Memory B cells: a proposed new immunological correlate for protective efficacy of Japanese encephalitis vaccine
Memory B cells induced by JE-ADVAX can provide protection against Japanese encephalitis virus in β2m-/- mice lacking CD8+ T cells, even when pre-challenge neutralizing antibodies are undetectable, highlighting memory B cells as a potential correlate of vaccine efficacy.
DOI: 10.1586/14760584.2013.814828 -
Vaccine-elicited SIV and HIV envelope-specific IgA and IgG memory B cells in rhesus macaque peripheral blood correlate with functional antibody responses and reduced viremia
The study develops a method to quantify rhesus macaque memory B cells and shows that vaccine-induced SIV/HIV envelope–specific IgG and IgA memory B cells correlate with functional antibody activities and reduced chronic viremia after challenge, supporting a role for humoral immu…
DOI: 10.1016/j.vaccine.2011.02.066 -
Correlating immunity with protection for HPV infection
This study investigates the correlation between immunity and protection against HPV infection, demonstrating that the quadrivalent HPV vaccine induces a strong and lasting immune response, particularly in prepubertal children.
DOI: 10.1016/s1201-9712(07)60016-2 -
Experimental studies on the efficacy and side-effects of intraperitoneal vaccination of Atlantic salmon (Salmo salarL.) against furunculosis
This study investigates the efficacy and side effects of various intraperitoneal vaccines against furunculosis in Atlantic salmon, demonstrating that mineral oil adjuvanted vaccines provide long-lasting protective immunity.
DOI: 10.1006/fsim.1996.0034 -
Identification of Surrogates and Correlates of Protection in Protective Immunity against Mycobacterium bovis Infection Induced in Neonatal Calves by Vaccination with M. bovis BCG Pasteur and M. bovis BCG Danish
This study compares the protective efficacy of neonatal vaccination with two Mycobacterium bovis BCG strains (Pasteur and Danish) in calves challenged with M. bovis, and identifies central memory IFN-γ–producing T cells as a key correlate of protection, with both vaccines reduci…
DOI: 10.1128/cvi.00543-10