A Phase 3b, Randomized, Open-Label Study to Evaluate the Safety and Immunogenicity of Select Travel Vaccines When Administered Concomitantly With MenACWY in Adults

• Sponsor: Novartis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01466387
• Collaborator: Novartis Vaccines (Industry)
• Enrollment: 552
• Locations: 5
• Arms: 6
• Duration (Months): 5
• Patients Per Site: 110.4
• Patients Per Site Per Month: 22.1

Study Details

Study Description

Brief Summary

This study compares the safety and immunogenicity profile of several travel vaccines given alone or concomitantly with MenACWY-CRM to healthy adults.

Condition or Disease	Intervention/Treatment	Phase
Meningococcal Disease; Meningococcal Meningitis; Typhoid; Yellow Fever; Rabies; Japanese Encephalitis	Biological: Typhoid Vi Polysaccharide Vaccine; Biological: Yellow Fever Vaccine; Biological: Japanese Encephalitis Vaccine; Biological: Rabies Vaccine; Biological: MenACWY-CRM Vaccine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 552 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase 3b, Randomized, Open-Label Study to Evaluate the Safety and Immunogenicity of Select Travel Vaccines When Administered Concomitantly With Novartis Meningococcal ACWY Conjugate Vaccine in Healthy Adults
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: TF+YF Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide and yellow fever vaccine.	Biological: Typhoid Vi Polysaccharide Vaccine; One dose of typhoid Vi polysaccharide vaccine.; Biological: Yellow Fever Vaccine; One dose of yellow fever vaccine.
Active Comparator: TF + YF + MenACWY-CRM197 Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.	Biological: Typhoid Vi Polysaccharide Vaccine; One dose of typhoid Vi polysaccharide vaccine.; Biological: Yellow Fever Vaccine; One dose of yellow fever vaccine.; Biological: MenACWY-CRM Vaccine; One dose of MenACWY-CRM vaccine.
Active Comparator: JE + Rabies Subjects ≥18 years to ≤60 years of age who received two doses of Japanese encephalitis and three doses of Rabies vaccine.	Biological: Japanese Encephalitis Vaccine; Two doses of Japanese Encephalitis Vaccine.; Biological: Rabies Vaccine; Three doses of Rabies vaccine.
Active Comparator: JE + Rab + MenACWY-CRM197 Subjects ≥18 years to ≤60 years of age who received two doses of Japanese encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.	Biological: Japanese Encephalitis Vaccine; Two doses of Japanese Encephalitis Vaccine.; Biological: Rabies Vaccine; Three doses of Rabies vaccine.; Biological: MenACWY-CRM Vaccine; One dose of MenACWY-CRM vaccine.
Active Comparator: Rabies Subjects ≥18 years to ≤60 years of age who received three doses of Rabies vaccine.	Biological: Rabies Vaccine; Three doses of Rabies vaccine.
Active Comparator: MenACWY-CRM197 (Combined) Subjects ≥18 years to ≤60 years of age who received one dose of meningococcal ACWY conjugate vaccine.	Biological: MenACWY-CRM Vaccine; One dose of MenACWY-CRM vaccine.

Outcome Measures

Primary Outcome Measures

1. Geometric Mean Anti-typhoid Vi Antibody Concentrations [Baseline and 1 month postvaccination (day 29).]

   Assessment was made to demonstrate the non-inferiority of the geometric mean anti-typhoid Vi antibody concentrations, 28 days after the vaccination of typhoid Vi polysaccharide (TF) and yellow fever (YF) vaccines given concomitantly with MenACWY-CRM197 to typhoid Vi polysaccharide and yellow fever vaccines given alone in healthy adults aged ≥18 years to ≤60 years.

2. Geometric Mean Anti-Yellow Fever Antibody Titer [Baseline and 1 month postvaccination (day 29).]

   Assessment was made to demonstrate the non-inferiority of the geometric mean anti-yellow fever antibody titers, 28 days after the vaccination of typhoid Vi polysaccharide (TF) and yellow fever (YF) vaccines given concomitantly with MenACWY-CRM197 to typhoid Vi polysaccharide and yellow fever vaccines given alone in healthy adults aged ≥18 years to ≤60 years.

3. Geometric Mean Anti-Japanese Encephalitis Neutralizing Antibody Titers [Baseline and 1 month post last vaccination (day 57).]

   Assessment was made to demonstrate the non-inferiority of the geometric mean anti-Japanese encephalitis neutralizing antibody titers, 28 days after the vaccination of the second dose of Japanese Encephalitis vaccine and third dose of the rabies virus vaccine given concomitantly with MenACWY-CRM197 or alone in healthy adults aged ≥18 years to ≤60 years.

4. Geometric Mean Anti-Rabies Virus Neutralizing Antibody Concentration [Baseline and 1 month post last vaccination (day 57).]

   Assessment was made to demonstrate the non-inferiority of the geometric mean anti-rabies virus neutralizing antibody concentrations, 28 days after the vaccination of the second dose of Japanese encephalitis vaccine and third dose of rabies virus vaccine given concomitantly with MenACWY-CRM197 or alone in healthy adults aged ≥18 years to ≤60 years.

Secondary Outcome Measures

1. Percentages Of Subjects With Anti-YF Neutralizing Antibody Titers ≥ 1/10, 28 Days After The Vaccination Of Typhoid Vi Polysaccharide And Yellow Fever, Concomitantly With MenACWY-CRM197 Or Given Alone [Baseline and 1 month postvaccination (day 29).]

   Immunogenicity was assessed as the percentages of subjects who achieved seroprotection as measured by neutralization test for anti-YF neutralizing antibody titers after the vaccination of typhoid Vi polysaccharide and yellow fever, given alone or concomitantly with MenACWY-CRM197 on day 29. Seroprotection is defined as percentages of subjects who achieved anti-YF neutralizing antibody titers ≥ 1/10 on day 29.

2. Percentages Of Subjects With Anti-JE Neutralizing Antibody Titers ≥ 1/10, 28 Days After The Vaccination Of The Last Doses Of Japanese Encephalitis And Rabies, Given Concomitantly With MenACWY-CRM197 Or Alone [Baseline and 1 month post last vaccination (day 57).]

   Immunogenicity was measured as the percentages of subjects who achieved seroprotection as measured by neutralization test for anti-Japanese encephalitis neutralizing antibody titers, 28 days after administration of the second dose of Japanese encephalitis virus vaccine and 28 days after the vaccination of third dose of rabies virus vaccine, given alone or concomitantly with MenACWY-CRM197. Seroprotection is defined as percentages of subjects who achieved anti-JE neutralizing titers ≥ 1/10 on Day 57.

3. Percentages Of Subjects With Anti-Rabies Virus Antibody Concentrations ≥ 0.5 IU/mL 28 Days After the Vaccination Of The Last Doses Of Japanese Encephalitis And Rabies Virus, Given Concomitantly With MenACWY-CRM197 Or Alone [Baseline and 1 month post last vaccination (day 57).]

   Immunogenicity was assessed as the percentages of subjects who achieved seroprotection as measured by neutralization test for anti-rabies neutralizing antibody titers, 28 days after administration of the second dose of Japanese encephalitis virus vaccine and 28 days after the vaccination of third dose of rabies virus vaccine, given alone or concomitantly with MenACWY-CRM197. Seroprotection is defined as a subject with a baseline hSBA titer < 1:4, seroresponse was defined as a post-vaccination hSBA titer ≥ 1:8; for a subject with a baseline hSBA titer ≥ 1:4, seroresponse was defined as a post-vaccination hSBA titer of at least 4 times the baseline.

4. Geometric Mean hSBA Titers For Meningococcal Serogroups A,C,W,Y 28 Days After The Vaccination Of MenACWY-CRM197 Given Concomitantly With Typhoid Vi Polysaccharide And Yellow Fever Vaccines Alone [Baseline and 1 month postvaccination (day 29).]

   Immunogenicity was assessed by Serum Bactericidal Assay using human complement (hSBA) geometric mean titers (GMTs) for meningococcal serogroups A,C,W,Y 28 days after administration of MenACWY-CRM197 given concomitantly with typhoid Vi polysaccharide and yellow fever vaccines or alone.

5. Seroresponse Rate For Meningococcal Serogroups A,C,W,Y 28 Days After Vaccination of MenACWY-CRM197 Given Concomitantly With Typhoid Vi Polysaccharide and Yellow Fever Vaccines or Alone [1 month postvaccination (day 29)]

   Immunogenicity was assessed by seroresponse rates as measured by human serum bactericidal activity (hSBA) titers for meningococcal serogroups A,C,W,Y 28 days after administration of MenACWY-CRM197 given concomitantly with typhoid Vi polysaccharide and yellow fever vaccines or alone. Seroresponse is defined as a postvaccination hSBA titer ≥1:8; for a subject with a baseline hSBA titer ≥1:4, seroresponse is defined as a postvaccination hSBA titer of at least four times the baseline.

6. Geometric Mean hSBA Titers for Meningococcal Serogroups A,C,W,Y 28 Days After the Vaccination of MenACWY-CRM197 Given Concomitantly With Japanese Encephalitis and Rabies Virus Vaccines or Alone [Baseline and 1 month post last vaccination (day 29 or day 57).]

   Immunogenicity was measured by human serum bactericidal activity (hSBA) geometric mean titers (GMTs) for meningococcal serogroups A,C,W,Y 28 days after administration of MenACWY-CRM197 given concomitantly with Japanese encephalitis and rabies virus vaccines or alone.

7. Seroresponse Rate for Meningococcal Serogroups A,C,W,Y 28 Days After Vaccination of MenACWY-CRM197 Given Concomitantly With Japanese Encephalitis and Rabies Virus Vaccines or Alone [1 month post last vaccination (day 29 or day 57)]

   Immunogenicity was assessed by seroresponse rates as measured by human serum bactericidal activity (hSBA) titers for meningococcal serogroups A,C,W,Y 28 days after administration of MenACWY-CRM197 given concomitantly with Japanese encephalitis and rabies virus vaccines or alone. Seroresponse is defined as a subject with a baseline hSBA titer < 1:4, seroresponse was defined as a post-vaccination hSBA titer ≥ 1:8; for a subject with a baseline hSBA titer ≥ 1:4, seroresponse was defined as a postvaccination hSBA titer of at least 4 times the baseline.

8. Geometric Mean Rabies Virus Neutralizing Antibody Concentration 28 Days After the Last Vaccination Of Rabies Virus Vaccine Concomitantly Either With Japanese Encephalitis or With Japanese Encephalitis And MenACWY-CRM197 [Baseline and 1 month post last vaccination (day 57).]

   The immunogenicity was assessed in rabies virus vaccine as measured by geometric mean rabies virus neutralizing antibody concentration, 28 days after vaccination of the third dose, when administered alone or concomitantly either with Japanese encephalitis vaccine or with Japanese Encephalitis and MenACWY-CRM197 vaccines.

9. Percentages of Subjects With Anti-rabies Virus Concentrations ≥ 0.5 IU/mL, 28 Days After the Last Vaccination of Rabies Virus Vaccine Concomitantly Either With Japanese Encephalitis or With Japanese Encephalitis and MenACWY-CRM197 [Baseline and 1 month post last vaccination (day 57).]

   Immunogenicity was measured as the percentages of subjects who achieved seroprotection of anti-rabies virus antibody concentrations 28 days after vaccination of the third dose of rabies virus vaccine, when administered alone or concomitantly either with Japanese encephalitis or with Japanese encephalitis and MenACWY-CRM197 vaccines. Seroprotection is defined as percentages of subjects who achieved anti-rabies virus antibody concentrations ≥ 0.5 IU/mL on day 57.

10. Number of Subjects With Adverse Events of Special Interest After Any Vaccination of Japanese Encephalitis and Rabies Virus Vaccines Given Concomitantly With MenACWY-CRM197 or Alone [day 1 to day 57 post last vaccination]

    In addition to the AEs and SAEs. Additional AESI were collected from day 1 to day 57 postvaccination in subjects after the vaccination of Japanese encephalitis and rabies virus vaccines given concomitantly with MenACWY-CRM197 or alone.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

Female and male subjects who must be healthy and must be:

1. Between 18 and 60 years of age inclusive and who have given their written informed consent;

2. Available for all visits and telephone calls scheduled for the study;

3. In good health as determined by medical history, physical examination and clinical judgment of the investigator;

4. For female subjects, having a negative urine pregnancy test.

Exclusion Criteria:

Individuals not eligible to be enrolled in the study are those:

1. who are breastfeeding;

2. who have a personal history of Neisseria meningitidis infection, typhoid fever, rabies, or any flavivirus infection (e.g., Japanese encephalitis, tick-borne encephalitis, yellow fever, dengue fever, West Nile virus infection);

3. who have been immunized with any of the study vaccines within the last five years as determined by medical history and/or vaccination card;

4. who have received investigational agents or vaccines within 30 days prior to enrollment or who expect to receive an investigational agent or vaccine prior to completion of the study;

5. who have received live licensed vaccines within 30 days and inactive vaccine within 15 days prior to enrollment or for whom receipt of a licensed vaccine is anticipated during the study period.

(Exception: Influenza vaccine may be administered up to 15 days prior to each study immunization and no less than 15 days after each study immunization);

1. who have received an anti-malaria drug, up to 2 months prior to the study;

2. who have experienced, within the 7 days prior to enrollment, significant acute infection (for example requiring systemic antibiotic treatment or antiviral therapy) or have experienced fever (defined as body temperature ≥ 38°C) within 3 days prior to enrollment;

3. who have any serious acute, chronic or progressive disease such as:

• history of cancer

• complicated diabetes mellitus

• advanced arteriosclerotic disease

• autoimmune disease

• HIV infection or AIDS

• blood dyscrasias

• congestive heart failure

• renal failure

• severe malnutrition (Note: Subjects with mild asthma are eligible for enrollment. Subjects with moderate or severe asthma requiring routine use of inhaled or systemic corticosteroids are not eligible for enrollment);

1. who have epilepsy, any progressive neurological disease or history of Guillain-Barre syndrome;

2. who have a history of anaphylaxis, serious vaccine reactions, or allergy to any vaccine component, including but not limited to latex allergy, egg allergy, antibiotic allergy, chicken proteins or gelatin allergy;

3. who have a known or suspected impairment/alteration of immune function, either congenital or acquired or resulting from (for example):

• receipt of immunosuppressive therapy within 30 days prior to enrollment (systemic corticosteroids administered for more than 5 days, or in a daily dose > 1 mg/kg/day prednisone or equivalent during any of 30 days prior to enrollment, or cancer chemotherapy);

• receipt of immunostimulants;

• receipt of parenteral immunoglobulin preparation, blood products, and/or plasma derivatives within 90 days prior to enrollment and for the full length of the study;

1. who are known to have a bleeding diathesis, or any condition that may be associated with a prolonged bleeding time;

2. who have myasthenia gravis; thyroid or thymic disorders,

3. who have any condition that, in the opinion of the investigator, might interfere with the evaluation of the study objectives;

4. who are part of the study personnel or close family members of those conducting this study.

5. for whom a long-term stay (≥ 1 month) was planned in Africa, Latin America, or Asia.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centrum ockovani a cestovni mediciny (Vaccination and Travel Medicine Centre) Poliklinika II	Bratri Stefanu 895	Hradec Kralove	Czech Republic	500 03
2	Berliner Centrum Fur Reise und Tropenmedizin	Jaegerstrasse 67-69	Berlin	Germany	10117
3		Bernhard Nocht Strasse 74	Hamburg	Germany	20359
4	University of Munich Georgenstr.5	Muenchen		Germany	80799
5	Universitat Rostock, Ernst Heydemann Str 6	Rostock		Germany	18057

Sponsors and Collaborators

• Novartis
• Novartis Vaccines

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT01466387
• Other Study ID Numbers: V59_38; 2011-000475-14
• First Posted: Nov 8, 2011
• Last Update Posted: Mar 11, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by Novartis: Adults; international travel vaccination; Meningococcal disease; meningococcal meningitis; typhoid; yellow fever; rabies; Japanese encephalitis
• Additional relevant MeSH terms: Rabies; Encephalitis, Japanese; Typhoid Fever; Yellow Fever; Meningococcal Infections; Meningitis, Meningococcal; Meningitis; Encephalitis; Vaccines

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled at 5 sites (Berhard Nocht Institut, Germany, Berliner Centrum fuer Reise, Germany, Universitat Rostock, Germany, University of Munich, Germany, Vacc and Travel Med. Center, Czech Republic)
Pre-assignment Detail	All enrolled subjects were included in the trial.

Arm/Group Title	TF+YF	TF+YF+MenACWY-CRM197	JE+Rabies	JE+Rabies+MenACWY-CRM197	Rabies	MenACWY-CRM197 (Combined)
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide and yellow fever vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese encephalitis and three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of meningococcal ACWY conjugate vaccine.
Period Title: Overall Study
STARTED	101	100	99	101	51	100
COMPLETED	100	100	98	99	51	99
NOT COMPLETED	1	0	1	2	0	1

Baseline Characteristics

Arm/Group Title	TF+YF	TF+YF+MenACWY-CRM197	JE+Rabies	JE+Rabies+MenACWY-CRM197	Rabies	MenACWY-CRM197 (Combined)	Total
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide and yellow fever vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese encephalitis and three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of meningococcal ACWY conjugate vaccine.	Total of all reporting groups
Overall Participants	101	100	99	101	51	100	552
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.5 (10.8)	35.1 (11.0)	35.0 (11.5)	35.0 (11.1)	35.8 (11.6)	36.9 (11.2)	35.7 (11.2)
Sex: Female, Male (Count of Participants)
Female	49 48.5%	44 44%	53 53.5%	50 49.5%	21 41.2%	50 50%	267 48.4%
Male	52 51.5%	56 56%	46 46.5%	51 50.5%	30 58.8%	50 50%	285 51.6%

Outcome Measures

1. Primary Outcome

Title	Geometric Mean Anti-typhoid Vi Antibody Concentrations
Description	Assessment was made to demonstrate the non-inferiority of the geometric mean anti-typhoid Vi antibody concentrations, 28 days after the vaccination of typhoid Vi polysaccharide (TF) and yellow fever (YF) vaccines given concomitantly with MenACWY-CRM197 to typhoid Vi polysaccharide and yellow fever vaccines given alone in healthy adults aged ≥18 years to ≤60 years.
Time Frame	Baseline and 1 month postvaccination (day 29).

Outcome Measure Data

Analysis Population Description

Analysis was done on the per-protocol (PP) set, ie, the subjects who received the vaccine correctly; provided evaluable serum samples at the relevant time points; and had no major protocol violations as defined prior to analysis.

Arm/Group Title	TF+YF	TF+YF+MenACWY-CRM197
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide and yellow fever vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.
Measure Participants	100	99
Day 1 (Typhoid Fever)	6.37	5.6
Day 29 (Typhoid Fever)	134	153

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TF+YF, TF+YF+MenACWY-CRM197
	Comments	The primary criterion for immunogenicity (postvaccination, day 29) was that the lower limit of the two-sided 95% confidence interval around the observed ratio of geometric mean concentrations between one dose of typhoid Vi polysaccharide and yellow fever vaccines given concomitantly with MenACWY-CRM197 to typhoid Vi polysaccharide and yellow fever vaccines given alone was greater than 0.5.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	GMC TF+YF+MenACWY-CRM/GMC TF+YF.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMC
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Geometric Mean Anti-Yellow Fever Antibody Titer
Description	Assessment was made to demonstrate the non-inferiority of the geometric mean anti-yellow fever antibody titers, 28 days after the vaccination of typhoid Vi polysaccharide (TF) and yellow fever (YF) vaccines given concomitantly with MenACWY-CRM197 to typhoid Vi polysaccharide and yellow fever vaccines given alone in healthy adults aged ≥18 years to ≤60 years.
Time Frame	Baseline and 1 month postvaccination (day 29).

Outcome Measure Data

Analysis Population Description

Analysis was done on the per-protocol (PP) set, ie, the subjects who received the vaccine correctly; provided evaluable serum samples at the relevant time points; and had no major protocol violations as defined prior to analysis.

Arm/Group Title	TF+YF	TF+YF+MenACWY-CRM197
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide and yellow fever vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.
Measure Participants	100	99
Day 1 (Yellow Fever)	9.05	12
Day 29 (Yellow Fever)	5244	5022

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TF+YF, TF+YF+MenACWY-CRM197
	Comments	The primary criterion for immunogenicity (postvaccination, day 29) was that the lower limit of the two sided 95% CI around the observed ratio of geometric mean titers between one dose of typhoid Vi polysaccharide and yellow fever vaccines given concomitantly with MenACWY-CRM197 to typhoid Vi polysaccharide and yellow fever vaccines given alone was greater than 0.5.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	GMT TF+YF+MenACWY/GMT TF+YF.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMT.
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Geometric Mean Anti-Japanese Encephalitis Neutralizing Antibody Titers
Description	Assessment was made to demonstrate the non-inferiority of the geometric mean anti-Japanese encephalitis neutralizing antibody titers, 28 days after the vaccination of the second dose of Japanese Encephalitis vaccine and third dose of the rabies virus vaccine given concomitantly with MenACWY-CRM197 or alone in healthy adults aged ≥18 years to ≤60 years.
Time Frame	Baseline and 1 month post last vaccination (day 57).

Outcome Measure Data

Analysis Population Description

Analysis was done on the PP set, i.e. the subjects who received the vaccine correctly; provided evaluable serum samples at the relevant time points; and had no major protocol violations as defined prior to analysis.

Arm/Group Title	JE+Rabies	JE+Rab+MenACWY-CRM197
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine and one dose of Meningococcal conjugate vaccine.
Measure Participants	96	97
Day 1 (Japanese Encephalitis)	5.61	5.58
Day 57 (Japanese Encephalitis)	183	165

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TF+YF, TF+YF+MenACWY-CRM197
	Comments	The primary criterion for immunogenicity (postvaccination, day 57) was that the lower limit of the two sided 95% CI around the observed ratio of geometric mean titers between the second dose of Japanese Encephalitis and third dose of rabies virus vaccines given concomitantly with MenACWY-CRM197 to Japanese Encephalitis and rabies virus vaccines given alone was greater than 0.5.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	GMT JE + Rab + MenACWY-CRM/GMT JE + Rab.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMT
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.7 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Geometric Mean Anti-Rabies Virus Neutralizing Antibody Concentration
Description	Assessment was made to demonstrate the non-inferiority of the geometric mean anti-rabies virus neutralizing antibody concentrations, 28 days after the vaccination of the second dose of Japanese encephalitis vaccine and third dose of rabies virus vaccine given concomitantly with MenACWY-CRM197 or alone in healthy adults aged ≥18 years to ≤60 years.
Time Frame	Baseline and 1 month post last vaccination (day 57).

Outcome Measure Data

Analysis Population Description

Analysis was done on the per-protocol (PP) set, i.e. the subjects who received the vaccine correctly; provided evaluable serum samples at the relevant time points; and had no major protocol violations as defined prior to analysis.

Arm/Group Title	JE+Rabies	JE+Rab+MenACWY-CRM197
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine and one dose of Meningococcal conjugate vaccine.
Measure Participants	96	97
Day 1 (Rabies)	0.056	0.049
Day 57 (Rabies)	12	11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TF+YF, TF+YF+MenACWY-CRM197
	Comments	The primary criterion for immunogenicity (postvaccination, day 57) was that the lower limit of the two sided 95% CI around the observed ratio of geometric mean concentrations between the second dose of Japanese encephalitis and third dose of rabies virus vaccines given concomitantly with MenACWY-CRM197 to Japanese encephalitis and rabies virus vaccines given alone was greater than 0.5.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	GMC JE + Rab + MenACWY-CRM/GMC JE + Rab.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMC
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentages Of Subjects With Anti-YF Neutralizing Antibody Titers ≥ 1/10, 28 Days After The Vaccination Of Typhoid Vi Polysaccharide And Yellow Fever, Concomitantly With MenACWY-CRM197 Or Given Alone
Description	Immunogenicity was assessed as the percentages of subjects who achieved seroprotection as measured by neutralization test for anti-YF neutralizing antibody titers after the vaccination of typhoid Vi polysaccharide and yellow fever, given alone or concomitantly with MenACWY-CRM197 on day 29. Seroprotection is defined as percentages of subjects who achieved anti-YF neutralizing antibody titers ≥ 1/10 on day 29.
Time Frame	Baseline and 1 month postvaccination (day 29).

Outcome Measure Data

Analysis Population Description

Analysis was done on the Modified-Intention to Treat (MITT) set, i.e. the subjects who provided evaluable serum samples whose assay results are available for at least one antigen on baseline and on at least one post-baseline visit.

Arm/Group Title	TF+YF	TF+YF+MenACWY-CRM197
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide and yellow fever vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.
Measure Participants	100	100
Day 1 (Yellow Fever)	34	36
Day 29 (Yellow Fever)	100	97

6. Secondary Outcome

Title	Percentages Of Subjects With Anti-JE Neutralizing Antibody Titers ≥ 1/10, 28 Days After The Vaccination Of The Last Doses Of Japanese Encephalitis And Rabies, Given Concomitantly With MenACWY-CRM197 Or Alone
Description	Immunogenicity was measured as the percentages of subjects who achieved seroprotection as measured by neutralization test for anti-Japanese encephalitis neutralizing antibody titers, 28 days after administration of the second dose of Japanese encephalitis virus vaccine and 28 days after the vaccination of third dose of rabies virus vaccine, given alone or concomitantly with MenACWY-CRM197. Seroprotection is defined as percentages of subjects who achieved anti-JE neutralizing titers ≥ 1/10 on Day 57.
Time Frame	Baseline and 1 month post last vaccination (day 57).

Outcome Measure Data

Analysis Population Description

The analysis was done on the MITT data set.

Arm/Group Title	JE+Rabies	JE+Rabies+MenACWY-CRM197
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.
Measure Participants	98	99
Day 1 (Japanese Encephalitis)	3	4
Day 57 (Japanese Encephalitis)	99	98

7. Secondary Outcome

Title	Percentages Of Subjects With Anti-Rabies Virus Antibody Concentrations ≥ 0.5 IU/mL 28 Days After the Vaccination Of The Last Doses Of Japanese Encephalitis And Rabies Virus, Given Concomitantly With MenACWY-CRM197 Or Alone
Description	Immunogenicity was assessed as the percentages of subjects who achieved seroprotection as measured by neutralization test for anti-rabies neutralizing antibody titers, 28 days after administration of the second dose of Japanese encephalitis virus vaccine and 28 days after the vaccination of third dose of rabies virus vaccine, given alone or concomitantly with MenACWY-CRM197. Seroprotection is defined as a subject with a baseline hSBA titer < 1:4, seroresponse was defined as a post-vaccination hSBA titer ≥ 1:8; for a subject with a baseline hSBA titer ≥ 1:4, seroresponse was defined as a post-vaccination hSBA titer of at least 4 times the baseline.
Time Frame	Baseline and 1 month post last vaccination (day 57).

Outcome Measure Data

Analysis Population Description

Analysis was done on the MITT data set.

Arm/Group Title	JE+Rabies	JE+Rabies+MenACWY-CRM197
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine and one dose of Meningococcal conjugate vaccine.
Measure Participants	98	99
Day 1 (Rabies)	3	1
Day 57 (Rabies)	100	100

8. Secondary Outcome

Title	Geometric Mean hSBA Titers For Meningococcal Serogroups A,C,W,Y 28 Days After The Vaccination Of MenACWY-CRM197 Given Concomitantly With Typhoid Vi Polysaccharide And Yellow Fever Vaccines Alone
Description	Immunogenicity was assessed by Serum Bactericidal Assay using human complement (hSBA) geometric mean titers (GMTs) for meningococcal serogroups A,C,W,Y 28 days after administration of MenACWY-CRM197 given concomitantly with typhoid Vi polysaccharide and yellow fever vaccines or alone.
Time Frame	Baseline and 1 month postvaccination (day 29).

Outcome Measure Data

Analysis Population Description

Analysis was done on the MITT data set.

Arm/Group Title	MenACWY-CRM197 (Combined)	TF+YF+MenACWY-CRM197
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received one dose of meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.
Measure Participants	99	100
Serogroup A (Day 1)	2.94	2.78
Serogroup A (Day 29)	65	62
Serogroup C (Day 1)	7.94	7.03
Serogroup C (Day 29)	49	54
Serogroup W (Day 1)	50	32
Serogroup W (Day 29)	129	211
Serogroup Y (Day 1)	7.61	7.76
Serogroup Y (Day 29)	89	78

9. Secondary Outcome

Title	Seroresponse Rate For Meningococcal Serogroups A,C,W,Y 28 Days After Vaccination of MenACWY-CRM197 Given Concomitantly With Typhoid Vi Polysaccharide and Yellow Fever Vaccines or Alone
Description	Immunogenicity was assessed by seroresponse rates as measured by human serum bactericidal activity (hSBA) titers for meningococcal serogroups A,C,W,Y 28 days after administration of MenACWY-CRM197 given concomitantly with typhoid Vi polysaccharide and yellow fever vaccines or alone. Seroresponse is defined as a postvaccination hSBA titer ≥1:8; for a subject with a baseline hSBA titer ≥1:4, seroresponse is defined as a postvaccination hSBA titer of at least four times the baseline.
Time Frame	1 month postvaccination (day 29)

Outcome Measure Data

Analysis Population Description

The analysis was done on the MITT data set.

Arm/Group Title	TF + YF + MenACWY-CRM197	MenACWY-CRM197 (Combined)
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of meningococcal ACWY conjugate vaccine.
Measure Participants	100	99
Serogroup A (Overall Seroresponse)	72	71
Serogroup C (Overall Seroresponse)	48	47
Serogroup W (Overall Seroresponse)	51	30
Serogroup Y (Overall Seroresponse)	63	66

10. Secondary Outcome

Title	Geometric Mean hSBA Titers for Meningococcal Serogroups A,C,W,Y 28 Days After the Vaccination of MenACWY-CRM197 Given Concomitantly With Japanese Encephalitis and Rabies Virus Vaccines or Alone
Description	Immunogenicity was measured by human serum bactericidal activity (hSBA) geometric mean titers (GMTs) for meningococcal serogroups A,C,W,Y 28 days after administration of MenACWY-CRM197 given concomitantly with Japanese encephalitis and rabies virus vaccines or alone.
Time Frame	Baseline and 1 month post last vaccination (day 29 or day 57).

Outcome Measure Data

Analysis Population Description

The analysis was done on the MITT data set.

Arm/Group Title	JE + Rab + MenACWY-CRM197	MenACWY-CRM197 (Combined)
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of meningococcal ACWY conjugate vaccine.
Measure Participants	99	99
Serogroup A (Day 1)	3.21	2.94
Serogroup A (Day 29 or Day 57)	32	65
Serogroup C (Day 1)	8.81	7.94
Serogroup C (Day 29 or Day 57)	44	49
Serogroup W (Day 1)	54	50
Serogroup W (Day 29 or Day 57)	119	129
Serogroup Y (Day 1)	8.11	7.61
Serogroup Y (Day 29 or Day 57)	55	89

11. Secondary Outcome

Title	Seroresponse Rate for Meningococcal Serogroups A,C,W,Y 28 Days After Vaccination of MenACWY-CRM197 Given Concomitantly With Japanese Encephalitis and Rabies Virus Vaccines or Alone
Description	Immunogenicity was assessed by seroresponse rates as measured by human serum bactericidal activity (hSBA) titers for meningococcal serogroups A,C,W,Y 28 days after administration of MenACWY-CRM197 given concomitantly with Japanese encephalitis and rabies virus vaccines or alone. Seroresponse is defined as a subject with a baseline hSBA titer < 1:4, seroresponse was defined as a post-vaccination hSBA titer ≥ 1:8; for a subject with a baseline hSBA titer ≥ 1:4, seroresponse was defined as a postvaccination hSBA titer of at least 4 times the baseline.
Time Frame	1 month post last vaccination (day 29 or day 57)

Outcome Measure Data

Analysis Population Description

The analysis was done on the MITT data set.

Arm/Group Title	JE + Rab + MenACWY-CRM197	MenACWY-CRM197 (Combined)
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received one dose of meningococcal ACWY conjugate vaccine.
Measure Participants	99	99
Serogroup A (Overall Seroresponse)	60	71
Serogroup C (Overall Seroresponse)	43	47
Serogroup W (Overall Seroresponse)	32	30
Serogroup Y (Overall Seroresponse)	56	66

12. Secondary Outcome

Title	Geometric Mean Rabies Virus Neutralizing Antibody Concentration 28 Days After the Last Vaccination Of Rabies Virus Vaccine Concomitantly Either With Japanese Encephalitis or With Japanese Encephalitis And MenACWY-CRM197
Description	The immunogenicity was assessed in rabies virus vaccine as measured by geometric mean rabies virus neutralizing antibody concentration, 28 days after vaccination of the third dose, when administered alone or concomitantly either with Japanese encephalitis vaccine or with Japanese Encephalitis and MenACWY-CRM197 vaccines.
Time Frame	Baseline and 1 month post last vaccination (day 57).

Outcome Measure Data

Analysis Population Description

The analysis was done on the MITT data set.

Arm/Group Title	JE + Rabies + MenACWY-CRM197	JE + Rabies	Rabies
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of rabies vaccine.	Subjects ≥18 years to ≤60 years of age who received three doses of Rabies vaccine
Measure Participants	99	98	51
Day 1 (Rabies)	0.051	0.057	0.068
Day 57 (Rabies)	11	11	8.97

13. Secondary Outcome

Title	Percentages of Subjects With Anti-rabies Virus Concentrations ≥ 0.5 IU/mL, 28 Days After the Last Vaccination of Rabies Virus Vaccine Concomitantly Either With Japanese Encephalitis or With Japanese Encephalitis and MenACWY-CRM197
Description	Immunogenicity was measured as the percentages of subjects who achieved seroprotection of anti-rabies virus antibody concentrations 28 days after vaccination of the third dose of rabies virus vaccine, when administered alone or concomitantly either with Japanese encephalitis or with Japanese encephalitis and MenACWY-CRM197 vaccines. Seroprotection is defined as percentages of subjects who achieved anti-rabies virus antibody concentrations ≥ 0.5 IU/mL on day 57.
Time Frame	Baseline and 1 month post last vaccination (day 57).

Outcome Measure Data

Analysis Population Description

The analysis was done on the MITT data set.

Arm/Group Title	JE + Rabies + MenACWY-CRM197	JE + Rabies	Rabies
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine.	Subjects ≥18 years to ≤60 yars of age who received three doses of Rabies vaccine.
Measure Participants	99	98	51
Day 1 (Rabies)	1	3	8
Day 57 (Rabies)	100	100	100

14. Secondary Outcome

Title	Number of Subjects With Adverse Events of Special Interest After Any Vaccination of Japanese Encephalitis and Rabies Virus Vaccines Given Concomitantly With MenACWY-CRM197 or Alone
Description	In addition to the AEs and SAEs. Additional AESI were collected from day 1 to day 57 postvaccination in subjects after the vaccination of Japanese encephalitis and rabies virus vaccines given concomitantly with MenACWY-CRM197 or alone.
Time Frame	day 1 to day 57 post last vaccination

Outcome Measure Data

Analysis Population Description

Analysis was done on the safety data set, i.e. the subjects in the exposed population who provided postvaccination safety data.

Arm/Group Title	JE + Rabies + MenACWY-CRM197	JE + Rabies
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.	Subjects ≥18 years to ≤60 years of age who received two doses of Japanese Encephalitis and three doses of Rabies vaccine.
Measure Participants	101	99
Injection site erythema	0	1
Hypersensitivity	1	0
Paresthesia	0	1
Erythema	1	0
Pruritus	1	1
Hot flush	1	0

Adverse Events

Time Frame	day 1 to day 29 (one month postvaccination); day 1 to day 57 (one month post last vaccination)
Adverse Event Reporting Description	AEs and SAEs were collected from day 1-29 for subjects vaccinated with typhoid Vi polysaccharide+YF +MenACWY-CRM197 or alone, from day 1-57 vaccinated with JE+rabies virus+MenACWY-CRM197 or alone and who received rabies vaccine alone.
Arm/Group Title	TF+YF		TF+YF+MenACWY-CRM197		JE+Rabies		JE+Rabies+MenACWY-CRM197		Rabies		MenACWY-CRM197 (Combined)
Arm/Group Description	Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide and yellow fever vaccine.		Subjects ≥18 years to ≤60 years of age who received one dose of typhoid Vi polysaccharide, yellow fever and meningococcal ACWY conjugate vaccine.		Subjects ≥18 years to ≤60 years of age who received two doses of Japanese encephalitis and three doses of Rabies vaccine.		Subjects ≥18 years to ≤60 years of age who received two doses of Japanese encephalitis and three doses of Rabies and one dose of meningococcal ACWY conjugate vaccine.		Subjects ≥18 years to ≤60 years of age who received three doses of Rabies vaccine.		Subjects ≥18 years to ≤60 years of age who received one dose of meningococcal ACWY conjugate vaccine.
All Cause Mortality
	TF+YF		TF+YF+MenACWY-CRM197		JE+Rabies		JE+Rabies+MenACWY-CRM197		Rabies		MenACWY-CRM197 (Combined)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	TF+YF		TF+YF+MenACWY-CRM197		JE+Rabies		JE+Rabies+MenACWY-CRM197		Rabies		MenACWY-CRM197 (Combined)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/101 (0%)		0/100 (0%)		1/99 (1%)		1/101 (1%)		0/51 (0%)		0/100 (0%)
Injury, poisoning and procedural complications
Injury	0/101 (0%)		0/100 (0%)		1/99 (1%)		0/101 (0%)		0/51 (0%)		0/100 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/101 (0%)		0/100 (0%)		0/99 (0%)		1/101 (1%)		0/51 (0%)		0/100 (0%)
Other (Not Including Serious) Adverse Events
	TF+YF		TF+YF+MenACWY-CRM197		JE+Rabies		JE+Rabies+MenACWY-CRM197		Rabies		MenACWY-CRM197 (Combined)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/101 (26.7%)		30/100 (30%)		23/99 (23.2%)		22/101 (21.8%)		9/51 (17.6%)		9/100 (9%)
General disorders
Injection site pain	12/101 (11.9%)		8/100 (8%)		6/99 (6.1%)		4/101 (4%)		2/51 (3.9%)		2/100 (2%)
Headache	7/101 (6.9%)		10/100 (10%)		9/99 (9.1%)		5/101 (5%)		5/51 (9.8%)		4/100 (4%)
Influenza like illness	5/101 (5%)		9/100 (9%)		5/99 (5.1%)		6/101 (5.9%)		0/51 (0%)		2/100 (2%)
Infections and infestations
Nasopharyngitis	3/101 (3%)		3/100 (3%)		3/99 (3%)		7/101 (6.9%)		2/51 (3.9%)		1/100 (1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.