Poliomyelitis
Conditions
Brief summary
The study will assess and compare the immune response to full-dose inactivated polio vaccines (IPV) via intramuscular (IM) administration and of the fractional dose of inactivated poliovirus vaccine (f-IPV) via intradermal (ID) administration, in different schedule combinations in the Expanded Program on Immunization (EPI) primary series.
Detailed description
This study prioritizes comparisons involving two-dose regimens recently recommended by the World Health Organization (WHO) Strategic Advisory Group of Experts on immunization (SAGE) and Pan American Health Organization (PAHO) in response to global IPV supply shortages 21. Furthermore, the study will provide data on the comparative humoral immunogenicity of various schedules to inform polio immunization policy for the post-eradication era. The study population will include infants in Dominican Republic and Panama. Absence of wild and circulating vaccine derived polioviruses along with the lack of regular Supplementary Immunization Activities (SIAs) in the Latin America region provide an ideal epidemiologic setting to study polio vaccine immunogenicity. Infants will receive two or three doses of full-dose IPV IM or f-IPV ID, in two schedules (10, 14 and 36 weeks and 14 and 36 weeks). Immunological and safety assessments will be made after one dose, two doses and three doses. A total of 773 infants will be enrolled and distributed into 4 groups, according to a randomization scheme. During the study period, infants will be administered other concomitant vaccines according to the national schedules of the participating countries, but the effect, if any, of the concomitant administration on IPV immunogenicity will not be assessed. Optimum immunogenicity expected from the dose(s) of IPV in the post-eradication era will have to be balanced with the cost and supply constraints of IPV. This study will be critical to determine how many doses of IPV and which schedule are optimal for the post-eradication era after the global cessation of Oral Polio Vaccine (OPV) use.
Interventions
BIOLOGICALIPV
Comparison of different vaccination schedules with 2 different vaccines (IPV and f-IPV) and 2 different types of administration (IM and ID)
BIOLOGICALf-IPV
Comparison of different vaccination schedules with 2 different vaccines (IPV and f-IPV) and 2 different types of administration (IM and ID)
Sponsors
Bill and Melinda Gates Foundation
Fidec Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Weeks to 7 Weeks
Healthy volunteers
Yes
Inclusion criteria
1. Infants of 6 weeks of age (-7 to + 7 days) on date of enrollment. 2. Healthy, as assessed from medical history and physical examination by a study physician, 3. Written informed consent obtained from parents or legal representatives who have been properly informed about the study and are able to comply with planned study procedures.
Exclusion criteria
1. Vaccinated with any poliovirus vaccine prior to inclusion, 2. A household contact with OPV vaccination history in the past 4 weeks, 3. HIV infection or pharmacologic immunosuppression, 4. Known allergy to any component of the study vaccines (phenoxyethanol, formaldehyde), 5. Uncontrolled coagulopathy or blood disorder contraindicating intramuscular and intradermal injections, 6. Acute severe febrile illness on day of vaccination deemed by the Investigator(s) to be a contraindication for vaccination, 7. Not suitable for inclusion or is unlikely to comply with the protocol in the opinion of the investigator(s).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 2 Doses IPV IM | To be assessed 4 weeks after the last dose | To determine if the seroconversion rate of a 2-dose intradermally administered fractional-dose inactivated poliovirus vaccine (f-IPV) regimen administered at 14 and 36 weeks of age is non-inferior to that of a 2-dose intramuscularly administered inactivated poliovirus vaccine (IPV) regimen administered at 14 and 36 weeks of age for poliovirus serotypes 1 and 2. |
| Seroconversion Non-inferiority of 2 Doses IPV IM vs 3 Doses IPV IM | To be assessed 4 weeks after the last dose | To determine if the seroconversion rate of a 2-dose IPV regimen administered at 14 and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen administered at 10, 14, and 36 weeks of age for poliovirus serotypes 1 and 2. |
| Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 3 Doses f-IPV ID | To be assessed 4 weeks after the last dose | To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks of age is non-inferior to that of a 3-dose f-IPV regimen administered at 10, 14, and 36 weeks of age for poliovirus serotypes 1 and 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 3 Doses IPV IM | To be assessed 4 weeks after the last dose | To determine if the seroconversion rate of a 3-dose f-IPV regimen administered at 10, 14, and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen also administered at 10, 14, and 36 weeks of age for poliovirus serotypes 1 and 2. |
| Seroconversion Superiority of 2 Doses IPV IM at Different Schedules | To be assessed 4 weeks after the second dose | To determine if the seroconversion rate of a 2-dose IPV regimen administered at 14 and 36 weeks of age is superior to that of a 2-dose IPV regimen administered at 10 and 14 weeks of age for poliovirus serotypes 1 and 2. |
| Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | 9 months | To assess the safety of each vaccine (IPV and f-IPV) as measured by the number of subjects experiencing serious adverse events (SAEs), important medical events (IMEs) and/or severe local reactions. This assessments is done in the Total Vaccinated Population (744 subjects). |
| Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 2 Doses IPV IM | To be assessed 4 weeks after the last dose | To determine if the seroconversion rate to a 3-dose regimen of f-IPV administered at 10, 14, and 36 weeks of age is non-inferior to that of a 2-dose IPV regimen administered at 14 and 36 weeks of age for poliovirus serotypes 1 and 2. |
| Seroconversion Superiority of 2 Dose f-IPV ID at Different Schedules | To be assessed 4 weeks after the second dose | To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks of age is superior to that of a 2-dose f-IPV regimen administered at 10 and 14 weeks of age for poliovirus serotypes 1 and 2. |
| Seroconversion Non-inferiority of 2 Dose f-IPV ID vs 3 Dose IPV IM | To be assessed 4 weeks after the last dose | To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen administered at 10, 14, and 36 weeks of age for poliovirus serotypes 1 and 2. |
Countries
Dominican Republic, Panama
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A 3 doses IPV IM at 10, 14 & 36 weeks of age incl. blood sampling at 10, 14, 18 & 40 weeks.
IPV: Comparison of different vaccination schedules with 2 different vaccines (IPV and f-IPV) and 2 different types of administration (IM and ID) | 200 |
| Group B 2 doses IPV IM at 14 & 36 weeks of age incl. blood sampling at 14, 18, 36 & 40 weeks.
IPV: Comparison of different vaccination schedules with 2 different vaccines (IPV and f-IPV) and 2 different types of administration (IM and ID) | 178 |
| Group C 3 doses f-IPV ID at 10, 14 & 36 weeks of age incl. blood sampling at 10, 14, 18 & 40 weeks.
f-IPV: Comparison of different vaccination schedules with 2 different vaccines (IPV and f-IPV) and 2 different types of administration (IM and ID) | 178 |
| Group D 2 doses f-IPV ID at 14 & 36 weeks of age incl. blood sampling at 14, 18, 36 & 40 weeks.
f-IPV: Comparison of different vaccination schedules with 2 different vaccines (IPV and f-IPV) and 2 different types of administration (IM and ID) | 217 |
| Total | 773 |
Baseline characteristics
| Characteristic | Group C | Group D | Total | Group A | Group B |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 178 Participants | 217 Participants | 773 Participants | 200 Participants | 178 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 7 Participants | 3 Participants | 15 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 101 Participants | 132 Participants | 446 Participants | 105 Participants | 108 Participants |
| Race/Ethnicity, Customized Latin American | 68 Participants | 78 Participants | 303 Participants | 88 Participants | 69 Participants |
| Race/Ethnicity, Customized White / Caucasian | 2 Participants | 4 Participants | 9 Participants | 3 Participants | 0 Participants |
| Region of Enrollment Dominican Republic | 85 participants | 117 participants | 386 participants | 88 participants | 96 participants |
| Region of Enrollment Panama | 93 participants | 100 participants | 387 participants | 112 participants | 82 participants |
| Sex: Female, Male Female | 82 Participants | 105 Participants | 372 Participants | 93 Participants | 92 Participants |
| Sex: Female, Male Male | 96 Participants | 112 Participants | 401 Participants | 107 Participants | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 195 | 0 / 172 | 0 / 170 | 0 / 207 |
| other Total, other adverse events | 7 / 195 | 0 / 172 | 4 / 170 | 2 / 207 |
| serious Total, serious adverse events | 12 / 195 | 7 / 172 | 9 / 170 | 9 / 207 |
Outcome results
Primary
Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 2 Doses IPV IM
To determine if the seroconversion rate of a 2-dose intradermally administered fractional-dose inactivated poliovirus vaccine (f-IPV) regimen administered at 14 and 36 weeks of age is non-inferior to that of a 2-dose intramuscularly administered inactivated poliovirus vaccine (IPV) regimen administered at 14 and 36 weeks of age for poliovirus serotypes 1 and 2.
Time frame: To be assessed 4 weeks after the last dose
Population: Per Protocol Population (692 subjects) is used for this assessment. The participants flow includes the Intended to Treat population (773 subjects).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group B | Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 2 Doses IPV IM | Serotype 1 | 98.1 percentage of seroconversion |
| Group B | Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 2 Doses IPV IM | Serotype 2 | 98.7 percentage of seroconversion |
| Group D | Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 2 Doses IPV IM | Serotype 1 | 95.9 percentage of seroconversion |
| Group D | Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 2 Doses IPV IM | Serotype 2 | 97.9 percentage of seroconversion |
Comparison: The group sizes are chosen to provide ≥ 80% power for each of the primary objectives, for the individual statistical tests of each serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual serotypes, and 39% for the combined serotypes.p-value: 0.05t-test, 1 sided
Primary
Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 3 Doses f-IPV ID
To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks of age is non-inferior to that of a 3-dose f-IPV regimen administered at 10, 14, and 36 weeks of age for poliovirus serotypes 1 and 2.
Time frame: To be assessed 4 weeks after the last dose
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group B | Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 3 Doses f-IPV ID | Serotype 1 | 98.8 percentage of seroconversion |
| Group B | Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 3 Doses f-IPV ID | Serotype 2 | 100 percentage of seroconversion |
| Group D | Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 3 Doses f-IPV ID | Serotype 1 | 95.9 percentage of seroconversion |
| Group D | Seroconversion Non-inferiority of 2 Doses f-IPV ID vs 3 Doses f-IPV ID | Serotype 2 | 97.9 percentage of seroconversion |
Comparison: The group sizes are chosen to provide ≥ 80% power for each of the primary objectives, for the individual statistical tests of each serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual serotypes, and 39% for the combined serotypes.p-value: 0.05t-test, 2 sided
Primary
Seroconversion Non-inferiority of 2 Doses IPV IM vs 3 Doses IPV IM
To determine if the seroconversion rate of a 2-dose IPV regimen administered at 14 and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen administered at 10, 14, and 36 weeks of age for poliovirus serotypes 1 and 2.
Time frame: To be assessed 4 weeks after the last dose
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group B | Seroconversion Non-inferiority of 2 Doses IPV IM vs 3 Doses IPV IM | Serotype 1 | 100 percentage of seroconversion |
| Group B | Seroconversion Non-inferiority of 2 Doses IPV IM vs 3 Doses IPV IM | Serotype 2 | 100 percentage of seroconversion |
| Group D | Seroconversion Non-inferiority of 2 Doses IPV IM vs 3 Doses IPV IM | Serotype 1 | 98.1 percentage of seroconversion |
| Group D | Seroconversion Non-inferiority of 2 Doses IPV IM vs 3 Doses IPV IM | Serotype 2 | 98.7 percentage of seroconversion |
Comparison: The group sizes are chosen to provide ≥ 80% power for each of the primary objectives, for the individual statistical tests of each serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual serotypes, and 39% for the combined serotypes.p-value: 0.05t-test, 2 sided
Secondary
Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions
To assess the safety of each vaccine (IPV and f-IPV) as measured by the number of subjects experiencing serious adverse events (SAEs), important medical events (IMEs) and/or severe local reactions. This assessments is done in the Total Vaccinated Population (744 subjects).
Time frame: 9 months
Population: Total Vaccinated Population (744 subjects) is used for safety analysis. The participants flow indicate the Intended To Treat population (773 subjects).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group B | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | SAE | 10 Participants |
| Group B | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | SLR | 0 Participants |
| Group B | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | IME | 4 Participants |
| Group D | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | SAE | 6 Participants |
| Group D | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | SLR | 0 Participants |
| Group D | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | IME | 0 Participants |
| Group C | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | IME | 2 Participants |
| Group C | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | SAE | 7 Participants |
| Group C | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | SLR | 0 Participants |
| Group D | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | SAE | 9 Participants |
| Group D | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | SLR | 0 Participants |
| Group D | Number of Participants Experiencing SAEs, IMEs and/or Severe Local Reactions | IME | 2 Participants |
Secondary
Seroconversion Non-inferiority of 2 Dose f-IPV ID vs 3 Dose IPV IM
To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen administered at 10, 14, and 36 weeks of age for poliovirus serotypes 1 and 2.
Time frame: To be assessed 4 weeks after the last dose
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group B | Seroconversion Non-inferiority of 2 Dose f-IPV ID vs 3 Dose IPV IM | Serotype 1 | 100 percentage of seroconversion |
| Group B | Seroconversion Non-inferiority of 2 Dose f-IPV ID vs 3 Dose IPV IM | Serotype 2 | 100 percentage of seroconversion |
| Group D | Seroconversion Non-inferiority of 2 Dose f-IPV ID vs 3 Dose IPV IM | Serotype 1 | 95.9 percentage of seroconversion |
| Group D | Seroconversion Non-inferiority of 2 Dose f-IPV ID vs 3 Dose IPV IM | Serotype 2 | 97.9 percentage of seroconversion |
Comparison: The group sizes are chosen to provide ≥ 80% power for each of the primary objectives, for the individual statistical tests of each serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual serotypes, and 39% for the combined serotypes.p-value: 0.05t-test, 2 sided
Secondary
Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 2 Doses IPV IM
To determine if the seroconversion rate to a 3-dose regimen of f-IPV administered at 10, 14, and 36 weeks of age is non-inferior to that of a 2-dose IPV regimen administered at 14 and 36 weeks of age for poliovirus serotypes 1 and 2.
Time frame: To be assessed 4 weeks after the last dose
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group B | Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 2 Doses IPV IM | Serotype 1 | 98.1 percentage of seroconversion |
| Group B | Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 2 Doses IPV IM | Serotype 2 | 98.7 percentage of seroconversion |
| Group D | Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 2 Doses IPV IM | Serotype 1 | 98.8 percentage of seroconversion |
| Group D | Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 2 Doses IPV IM | Serotype 2 | 100 percentage of seroconversion |
Comparison: The group sizes are chosen to provide ≥ 80% power for each of the primary objectives, for the individual statistical tests of each serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual serotypes, and 39% for the combined serotypes.p-value: 0.05t-test, 2 sided
Secondary
Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 3 Doses IPV IM
To determine if the seroconversion rate of a 3-dose f-IPV regimen administered at 10, 14, and 36 weeks of age is non-inferior to that of a 3-dose IPV regimen also administered at 10, 14, and 36 weeks of age for poliovirus serotypes 1 and 2.
Time frame: To be assessed 4 weeks after the last dose
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group B | Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 3 Doses IPV IM | Serotype 1 | 100 percentage of seroconversion |
| Group B | Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 3 Doses IPV IM | Serotype 2 | 100 percentage of seroconversion |
| Group D | Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 3 Doses IPV IM | Serotype 1 | 98.8 percentage of seroconversion |
| Group D | Seroconversion Non Inferiority of 3 Doses f-IPV ID vs 3 Doses IPV IM | Serotype 2 | 100 percentage of seroconversion |
Comparison: The group sizes are chosen to provide ≥ 80% power for each of the primary objectives, for the individual statistical tests of each serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual serotypes, and 39% for the combined serotypes.p-value: 0.05t-test, 2 sided
Secondary
Seroconversion Superiority of 2 Dose f-IPV ID at Different Schedules
To determine if the seroconversion rate of a 2-dose f-IPV regimen administered at 14 and 36 weeks of age is superior to that of a 2-dose f-IPV regimen administered at 10 and 14 weeks of age for poliovirus serotypes 1 and 2.
Time frame: To be assessed 4 weeks after the second dose
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group B | Seroconversion Superiority of 2 Dose f-IPV ID at Different Schedules | Serotype 1 | 83.2 percentage of seroconversion |
| Group B | Seroconversion Superiority of 2 Dose f-IPV ID at Different Schedules | Serotype 2 | 83.9 percentage of seroconversion |
| Group D | Seroconversion Superiority of 2 Dose f-IPV ID at Different Schedules | Serotype 1 | 95.9 percentage of seroconversion |
| Group D | Seroconversion Superiority of 2 Dose f-IPV ID at Different Schedules | Serotype 2 | 97.9 percentage of seroconversion |
Comparison: The group sizes are chosen to provide ≥ 80% power for each of the primary objectives, for the individual statistical tests of each serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual serotypes, and 39% for the combined serotypes.p-value: 0.0001Fisher Exact
Secondary
Seroconversion Superiority of 2 Doses IPV IM at Different Schedules
To determine if the seroconversion rate of a 2-dose IPV regimen administered at 14 and 36 weeks of age is superior to that of a 2-dose IPV regimen administered at 10 and 14 weeks of age for poliovirus serotypes 1 and 2.
Time frame: To be assessed 4 weeks after the second dose
Population: Per Protocol Population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group B | Seroconversion Superiority of 2 Doses IPV IM at Different Schedules | Serotype 1 | 95.6 percentage of seroconversion |
| Group B | Seroconversion Superiority of 2 Doses IPV IM at Different Schedules | Serotype 2 | 88.9 percentage of seroconversion |
| Group D | Seroconversion Superiority of 2 Doses IPV IM at Different Schedules | Serotype 1 | 98.1 percentage of seroconversion |
| Group D | Seroconversion Superiority of 2 Doses IPV IM at Different Schedules | Serotype 2 | 98.7 percentage of seroconversion |
Comparison: The group sizes are chosen to provide ≥ 80% power for each of the primary objectives, for the individual statistical tests of each serotype, as well as across both serotypes simultaneously. Power of ≥80% is also available for all secondary objectives, except for the comparison of the f-IPV regimen administered at weeks 14 and 36 to the 3-dose IPV regimen, which has power of 62% for individual serotypes, and 39% for the combined serotypes.p-value: 0.0001Fisher Exact