# Clinical Efficacy of Tozinameran in COVID-19 Prevention

## What clinical efficacy data support Tozinameran's prevention of COVID-19?

Randomized controlled trials enrolling over 46,000 participants and real-world observational studies including millions of individuals demonstrate that Tozinameran prevents COVID-19 with 91-95% efficacy against symptomatic infection and over 95% efficacy against severe disease, hospitalization, and death across age groups and SARS-CoV-2 variants.

## Abstract

Tozinameran demonstrated 95% efficacy (95% CI: 90.3-97.6) against laboratory-confirmed COVID-19 in phase 3 randomized controlled trials, with real-world observational studies confirming 91-95.3% effectiveness. Protection against severe outcomes was exceptionally high, with efficacy of 96.7% against severe disease, 94.3% against hospitalization, and 96.1% against COVID-19-related death. The vaccine also prevented asymptomatic infection with 89-91% efficacy. Efficacy declined gradually from 96.2% in the first two months to 83.7% after four months following the second dose, but a third booster dose administered at a median of 10.8 months restored efficacy to 95.3%. The vaccine maintained substantial protection across SARS-CoV-2 variants, including 100% efficacy against the B.1.351 (beta) variant in South Africa, 85-97% against B.1.1.7 (alpha), and 81-96% against Delta.

## Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 8 key aspects that mattered most to the research question.

### Records from Elicit search
- **n** = 200  
- Papers screened using: Primary Intervention, Clinical Efficacy Outcomes, Study Design, Comparative Design, Study Population, Beyond Safety/Immunogenicity Only, Human Clinical Research, Isolatable Tozinameran Effects
- **n** = 200  
- Papers screened out  
- **n** = 190  
- Papers included for extraction  
- **n** = 10

### Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine.

We ran this query: "What clinical efficacy data support Tozinameran’s prevention of COVID-19?"

The search returned 200 total results from Elicit.

We retrieved 200 papers most relevant to the query for screening.

## Screening

We screened in sources based on their abstracts that met these criteria:
- **Primary Intervention**: Does this study investigate Tozinameran (BNT162b2, Pfizer-BioNTech COVID-19 vaccine) as the primary intervention?  
- **Clinical Efficacy Outcomes**: Does this study report clinical efficacy outcomes for COVID-19 prevention with laboratory-confirmed infection as the outcome measure?  
- **Study Design**: Is this study a randomized controlled trial, cohort study, case-control study, systematic review, or meta-analysis?  
- **Comparative Design**: Does this study compare Tozinameran to placebo, other COVID-19 vaccines, or unvaccinated controls?  
- **Study Population**: Does this study include participants of any age group eligible for Tozinameran vaccination?  
- **Beyond Safety/Immunogenicity Only**: Does this study report clinical efficacy outcomes (not solely immunogenicity, safety, or adverse events without efficacy data)?  
- **Human Clinical Research**: Is this a human clinical study?  
- **Isolatable Tozinameran Effects**: Can the effects of Tozinameran be isolated in this study?

## Data extraction

### Study Design

- Extract the study design and key methodological details that establish the strength of clinical efficacy evidence for Tozinameran.

### Study Population

- Extract details about the study population relevant to Tozinameran efficacy for COVID-19 prevention.

### Prevention Outcomes

- Extract all COVID-19 prevention outcomes measured for Tozinameran.

### Efficacy Results

- Extract quantitative efficacy/effectiveness results for Tozinameran in preventing COVID-19.

### Follow-up Duration

- Extract follow-up duration details relevant to Tozinameran’s clinical efficacy for COVID-19 prevention.

### Variant Context

- Extract information about SARS-CoV-2 variants and epidemiological context during the study period.

### Safety Profile

- Extract safety data relevant to the clinical efficacy assessment of Tozinameran.

### Subgroup Analysis

- Extract efficacy results for clinically relevant subgroups that inform Tozinameran’s prevention efficacy.

## Results

### Characteristics of Included Studies
| Study                               | Full text retrieved? | Study Type                                    | Sample Size          | Population                | Geographic Location | Follow-up Duration  | Predominant Variant                         |
|-------------------------------------|---------------------|-----------------------------------------------|----------------------|---------------------------|---------------------|---------------------|--------------------------------------------|
| F. Polack et al., 2020             | Yes                 | Randomized Controlled Trial, observer-blinded, placebo-controlled | 43,548 participants   | Persons ≥16 years       | Multinational       | Median 2 months     | Not reported                                |
| Stephen J. Thomas et al., 2021     | Yes                 | Randomized Controlled Trial, observer-blinded, placebo-controlled | 46,429 participants   | Persons ≥12 years       | Multinational       | 6 months            | B.1.351 (beta) in South Africa            |
| S. J. Thomas et al., 2021          | Yes                 | Randomized Controlled Trial, observer-blinded transitioning to open-label | 46,429 participants    | Persons ≥12 years, healthy or stable chronic conditions | Multinational       | Up to 6 months       | B.1.351 (beta) in South Africa            |
| E. Moreira et al., 2022            | No                  | Randomized Controlled Trial, placebo-controlled | 10,125 participants   | Persons ≥16 years who received two doses ≥6 months prior | Not specified        | Median 2.5 months    | Not reported                                |
| Eric J. Haas et al., 2021          | Yes                 | Observational study                           | 6.5 million residents | Residents of Israel ≥16 years | Israel             | Median 7 weeks after second dose | B.1.1.7 (94.5% prevalence)                  |
| G. Chodick et al., 2021            | Yes                 | Historical cohort study                      | 1,178,597 individuals | MHS members ≥16 years    | Israel             | 7-27 days after second dose | Not specified                              |
| Noa Dagan et al., 2021             | Yes                 | Cohort study with matched controls          | 596,618 per study group  | Newly vaccinated persons ≥16 years | Israel             | December 2020 - February 2021 | Not reported                             |
| R. Frenck et al., 2021             | No                  | Randomized Controlled Trial, observer-blinded, placebo-controlled | 2,260 adolescents      | Adolescents 12-15 years   | Multinational       | Not specified      | Not reported                               |
| V. Hall et al., 2021               | Yes                 | Prospective cohort study                     | 23,324 participants   | Healthcare workers ≥18 years (median age 46.1 years, 84% female) | England              | December 2020 - February 2021 (approximately 2 months) | B.1.1.7 (dominant)  |
| Megan Wallace et al., 2022          | Yes                 | Systematic review and meta-analysis of observational studies | 26 studies included    | Persons ≥16 years, general population and sub-populations | Various countries    | Studies through August 2021 | Delta variant predominant in some studies |

The included studies comprised three phase 3 randomized controlled trials of the primary two-dose series, one RCT of a third booster dose, one adolescent-focused RCT, four real-world observational effectiveness studies, and one systematic review. The studies evaluated populations ranging from adolescents to elderly adults across multiple geographic regions, with sample sizes from 2,260 to 6.5 million participants. Follow-up durations ranged from 2 months to 6 months in the RCTs. The observational studies were conducted primarily during periods when B.1.1.7 (alpha) variant was predominant, while one RCT included data from South Africa during B.1.351 (beta) variant predominance.

### Efficacy Against Laboratory-Confirmed COVID-19

#### Primary Two-Dose Series Efficacy
| Study                               | Outcome                        | Time Point                   | Efficacy (95% CI)         | Cases (Vaccine/Placebo)    |
|-------------------------------------|--------------------------------|-----------------------------|----------------------------|-----------------------------|
| F. Polack et al., 2020             | Laboratory-confirmed COVID-19  | ≥7 days after dose 2         | 95% (90.3-97.6)            | 8/162                       |
| Stephen J. Thomas et al., 2021     | Laboratory-confirmed COVID-19  | Through 6 months             | 91.3% (89.0-93.2)         | Not specified                |
| S. J. Thomas et al., 2021          | Laboratory-confirmed COVID-19  | Through 6 months             | 91% (89.0-93.2)           | Not specified                |
| Eric J Haas et al., 2021          | SARS-CoV-2 infection           | ≥7 days after dose 2         | 95.3% (94.9-95.7)         | Incidence: 3.1 vs 91.5 per 100,000 person-days |
| Eric J Haas et al., 2021          | Symptomatic COVID-19           | ≥7 days after dose 2         | 97.0% (96.7-97.2)         | Incidence: 0.8 vs 32.5 per 100,000 person-days |
| G. Chodick et al., 2021            | SARS-CoV-2 infection           | 7-27 days after dose 2       | 90% (79-95)               | Incidence: 5.4 vs 54.8 per 100,000 |
| G. Chodick et al., 2021            | COVID-19                        | 7-27 days after dose 2       | 94% (88-97)               | Not specified                |
| Noa Dagan et al., 2021             | Documented infection           | ≥7 days after dose 2         | 92% (88-95)               | Not specified                |
| Noa Dagan et al., 2021             | Symptomatic COVID-19          | ≥7 days after dose 2         | 94% (87-98)               | Not specified                |
| V. Hall et al., 2021               | SARS-CoV-2 infection (PCR-confirmed) | ≥7 days after dose 2 | 85% (74-96)               | Incidence: 4 vs 14 per 10,000 person-days |

The primary two-dose series demonstrated consistently high efficacy against laboratory-confirmed COVID-19 across both randomized controlled trials and real-world observational studies. The pivotal RCT by Polack et al. showed 95% efficacy, which was closely replicated in the Israeli national observational studies at 95.3% and 90%. Efficacy against symptomatic COVID-19 was particularly high at 94-97%. The meta-analysis of 8 studies confirmed pooled efficacy of 92.4% against symptomatic COVID-19. Among healthcare workers in England, where B1.1.7 variant was dominant, effectiveness was 85% seven days after the second dose.

#### Temporal Trends in Efficacy
| Time Interval                     | Efficacy (95% CI)             | Study                               |
|----------------------------------|--------------------------------|-------------------------------------|
| Dose 1 to dose 2               | 58.4% (40.8-71.2)             | Stephen J. Thomas et al., 2021     |
| 7 days to <2 months after dose 2 | 96.2% (93.3-98.1)             | Stephen J. Thomas et al., 2021     |
| 2 months to <4 months after dose 2 | 90.1% (86.6-92.9)         | Stephen J. Thomas et al., 2021     |
| ≥4 months after dose 2           | 83.7% (74.7-89.9)             | Stephen J. Thomas et al., 2021     |

There was evidence of gradual waning in vaccine efficacy over time. Efficacy peaked at 96.2% in the first two months after the second dose, declined to 90.1% between 2-4 months, and decreased further to 83.7% after 4 months. This represented approximately 6% decline in efficacy every 2 months, though protection remained substantial throughout the 6-month follow-up period.

#### Third (Booster) Dose Efficacy

The study by Moreira et al. evaluated a third booster dose administered a median of 10.8 months after the second dose. Among participants without evidence of previous SARS-CoV-2 infection, COVID-19 occurred in 6 vaccine recipients versus 123 placebo recipients, yielding a relative vaccine efficacy of 95.3% (95% CI: 89.5-98.3). This efficacy was assessed over a median follow-up of 2.5 months and demonstrated restoration of high-level protection comparable to the initial two-dose series.

### Efficacy Against Severe Disease Outcomes
| Study                               | Outcome                | Efficacy (95% CI) | Time Point                    |
|-------------------------------------|-----------------------|--------------------|------------------------------|
| F. Polack et al., 2020             | Severe COVID-19       | Not quantified      | ≥7 days after dose 2        |
| Stephen J. Thomas et al., 2021     | Severe disease         | 96.7% (80.3-99.9)  | Through 6 months             |
| S. J. Thomas et al., 2021          | Severe disease         | 97% (80.3-99.9)    | Through 6 months             |
| Eric J Haas et al., 2021          | Severe or critical COVID-19 hospitalization | 97.5% (97.1-97.8)  | ≥7 days after dose 2        |
| Eric J Haas et al., 2021          | COVID-19-related hospitalization | 97.2% (96.8-97.5) | ≥7 days after dose 2        |
| G. Chodick et al., 2021            | Hospitalization (age 45-64) | 55% reduction (HR 0.45, 95% CI: 0.23-0.90) | 7-27 days after dose 2      |
| G. Chodick et al., 2021            | Hospitalization (age ≥75) | 44% reduction (HR 0.56, 95% CI: 0.36-0.89) | 7-27 days after dose 2      |
| Noa Dagan et al., 2021             | Hospitalization        | 87% (55-100)     | ≥7 days after dose 2        |
| Noa Dagan et al., 2021             | Severe disease         | 92% (75-100)      | ≥7 days after dose 2        |
| Megan Wallace et al., 2022          | Hospitalization due to COVID-19 | 94.3% (87.9-97.3) | Meta-analysis (8 studies)   |

Efficacy against severe disease outcomes consistently exceeded 90% across multiple studies. The Israeli national surveillance data demonstrated 97.2% efficacy against COVID-19-related hospitalization and 97.5% against severe or critical hospitalization. The 6-month RCT follow-up confirmed 96.7% efficacy against severe disease. The meta-analysis pooled estimate showed 94.3% efficacy against hospitalization. Notably, protection against severe outcomes appeared more durable than protection against infection, with high efficacy maintained throughout the 6-month follow-up period.

### Efficacy Against Death
| Study                               | Outcome                     | Efficacy (95% CI)  | Time Point                    |
|-------------------------------------|----------------------------|---------------------|------------------------------|
| Eric J Haas et al., 2021          | COVID-19-related death      | 96.7% (96.0-97.3)   | ≥7 days after dose 2        |
| Eric J Haas et al., 2021          | Deaths                      | 98.1%               | ≥14 days after dose 2       |
| Eric J Haas et al., 2021          | Deaths                      | 77.0%               | 14-21 days after dose 1     |
| G. Chodick et al., 2021            | Deaths during protection period | Not quantified  | 7-27 days after dose 2      |
| Noa Dagan et al., 2021             | Death from COVID-19        | 72% (19-100)        | Days 14-20 after dose 1     |
| Megan Wallace et al., 2022          | Death due to COVID-19      | 96.1% (91.5-98.2)   | Meta-analysis (4 studies)    |

Efficacy against COVID-19-related death was exceptionally high. The Israeli national data showed 96.7% efficacy at 7 or more days after the second dose, increasing to 98.1% at 14 or more days. The meta-analysis of four studies confirmed 96.1% pooled efficacy against death. Even after a single dose, efficacy against death reached 72-77%, demonstrating substantial early protection against the most severe outcome.

### Efficacy Against Asymptomatic Infection
| Study                               | Outcome                          | Efficacy (95% CI)       | Time Point                    |
|-------------------------------------|----------------------------------|--------------------------|------------------------------|
| Eric J Haas et al., 2021          | Asymptomatic SARS-CoV-2 infection | 91.5% (90.7-92.2)       | ≥7 days after dose 2        |
| Megan Wallace et al., 2022          | Asymptomatic SARS-CoV-2 infection | 89.3%                  | Meta-analysis (2 studies)   |

The vaccine demonstrated high efficacy against asymptomatic infection, with Israeli surveillance data showing 91.5% efficacy and the meta-analysis confirming 89.3% pooled efficacy. This finding from healthcare workers undergoing regular asymptomatic testing suggests the vaccine substantially reduces transmission potential by preventing asymptomatic carriage. However, the meta-analysis rated this evidence as very low certainty, likely due to the limited number of studies and challenges in ascertaining truly asymptomatic cases.

### Variant-Specific Efficacy

The B.1.351 (beta) variant, which showed reduced neutralization by vaccine-induced sera in laboratory studies, remained susceptible to clinical protection. In South Africa, where beta variant was predominant, vaccine efficacy was 100% (95% CI: 53.5-100). All sequenced COVID-19 cases in South Africa were confirmed to be B.1.351 lineage, and despite theoretical concerns about immune evasion, the vaccine maintained complete clinical protection.

The B.1.1.7 (alpha) variant was the dominant strain during the Israeli observational studies, with an estimated prevalence of 94.5%, and among healthcare workers in England. The consistently high effectiveness observed in these populations (85-97%) demonstrated robust protection against this variant.

For the Delta variant, the meta-analysis included studies from the Delta-dominant period showing variant-specific efficacy of 81.2% (95% CI: 50.2-92.9) against symptomatic COVID-19, 96% against hospitalization, and 36-74% against asymptomatic infection. While these estimates were somewhat lower than overall pooled estimates, particularly for asymptomatic infection, substantial protection remained against severe outcomes.

### Age-Specific Efficacy
| Age Group          | Outcome         | Efficacy (95% CI)         | Study                             |
|------------------|----------------|----------------------------|----------------------------------|
| 12-15 years      | COVID-19       | 100% (75.3-100)           | R. Frenck et al., 2021            |
| 16-44 years      | Infection      | 92% (83-96)               | G. Chodick et al., 2021           |
| 45-64 years      | Infection      | 90% (80-95)               | G. Chodick et al., 2021           |
| 65-74 years      | Infection      | 82% (63-92)               | G. Chodick et al., 2021           |
| ≥75 years        | Infection      | 82% (61-91)               | G. Chodick et al., 2021           |
| ≥85 years        | All outcomes   | Highly effective           | Eric J Haas et al., 2021         |

Efficacy was maintained across all age groups from adolescents to the elderly, though some attenuation was observed in older adults. The adolescent trial demonstrated 100% efficacy with no COVID-19 cases among vaccinated participants. In 12-to-15-year-olds, the immune response exceeded that of 16-to-25-year-olds (geometric mean ratio 1.76, 95% CI: 1.47-2.10), suggesting particularly robust immunogenicity in this younger age group.

Among adults, efficacy against infection was highest in younger age groups at 92% and declined modestly with age to 82% in those 65 years and older. Nevertheless, the vaccine remained highly effective in preventing severe disease across all ages, including the oldest adults aged 85 years and above. The 6-month RCT confirmed generally 90-100% efficacy across age subgroups.

### Efficacy in Special Populations

#### Immunocompromised Individuals

Vaccine effectiveness was notably reduced in immunocompromised populations. Among immunosuppressed patients, overall effectiveness against infection was 71% (95% CI: 37-87), substantially lower than the 90% observed in the general population. This attenuation was more pronounced in older immunosuppressed individuals, with effectiveness of only 52% (95% CI: -26 to 82) in those aged 65 and older.

#### Healthcare Workers

The prospective cohort study among 23,324 healthcare workers in England showed vaccine effectiveness of 70% (95% CI: 55-85) at 21 days after the first dose and 85% (95% CI: 74-96) at 7 days after the second dose. Healthcare workers with previous infection had 90% immune protection compared to the negative cohort.

#### Previously Infected vs. Naive Individuals

Among participants with previous SARS-CoV-2 infection, natural infection conferred approximately 72.6% protection. The vaccine was effective in preventing further infections in previously infected individuals, supporting vaccination without requiring screening for prior infection.

#### Patients with Comorbidities

Among patients with diabetes and cardiovascular diseases, vaccine effectiveness was approximately 82% (95% CI: 62-92), slightly lower than the general population but still indicating substantial protection.

## Safety Profile

The vaccine demonstrated a favorable safety profile across all studies. Reactogenicity was predominantly mild to moderate, with the most common events being injection-site pain (79-86%), fatigue (60-66%), and headache (55-65%). These reactions were short-term and transient.

Serious adverse events were rare and occurred at similar rates in vaccine and placebo groups. In the pivotal trial, the incidence of serious adverse events was low and similar between groups. Through 6 months of follow-up, few participants experienced adverse events leading to study withdrawal. Death rates were comparable between vaccinated and control groups.

For the third booster dose, local and systemic reactogenicity events were generally of low grade, with no new safety signals identified and no cases of myocarditis or pericarditis reported. The consistent safety profile across the primary series and booster dose supports the vaccine’s favorable benefit-risk profile for COVID-19 prevention.

## Synthesis

The body of evidence for Tozinameran’s clinical efficacy in preventing COVID-19 demonstrates remarkable consistency across diverse study designs, populations, and geographic settings. The convergence of findings from phase 3 RCTs showing 95% efficacy and real-world observational studies in Israel showing 95.3% effectiveness provides strong support for the vaccine’s protection against laboratory-confirmed COVID-19.

Several apparent heterogeneities in the results can be explained by methodological and contextual factors. The lower effectiveness observed among healthcare workers in England (85%) compared to the general Israeli population (95.3%) likely reflects both the high-exposure occupational setting and the timing of assessment, as the healthcare worker study measured effectiveness shortly after dose 2.

The gradual decline in efficacy over time—from 96.2% in the first 2 months to 83.7% after 4 months—represents genuine waning immunity rather than measurement artifact. This temporal pattern was consistent across the extended RCT follow-up and provides biological plausibility for the observed restoration of high-level protection (95.3%) following booster dose administration at a median of 10.8 months.

The vaccine’s favorable safety profile, with predominantly mild and transient reactogenicity and no significant safety signals, supports its positive benefit-risk profile for preventing COVID-19 across diverse populations.