48
ORIGINAL ARTICLE
Safety and Immunogenicity of Typhoid Fever and Yellow Fever Vaccines When Administered Concomitantly With Quadrivalent Meningococcal ACWY Glycoconjugate Vaccine in Healthy Adults Martin Alberer, MD,∗ Gerd Burchard, MD,† Tomas Jelinek, MD,‡ Emil Reisinger, MD,§ Jiri Beran, MD,|| Lucie Cerna Hlavata, MD,¶ Eduardo Forleo-Neto, MD,¶ Alemnew F. Dagnew, MD,¶ and Ashwani K. Arora, MD# of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany; † University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ‡ Berlin Center for Travel and Tropical Medicine, Berlin, Germany; § Department of Tropical Medicine and Infectious Diseases, University of Rostock Medical School, Rostock, Germany; || Vaccination and Travel Medicine Centre, Hradec Kralove, Czech Republic; ¶ Novartis Vaccines and Diagnostics Inc., Cambridge, MA, USA; # Novartis Vaccines and Diagnostics S.r.l., Sienna, Italy ∗ Department
DOI: 10.1111/jtm.12164
Background. Compact and short pre-travel immunization schedules, which include several vaccinations in a single visit, are desirable for many travelers. However, concomitant vaccination could potentially compromise immunogenicity and/or safety of the individual vaccines and, therefore, possible vaccine interferences should be carefully assessed. This article discusses the immunogenicity and safety of travel vaccines for typhoid fever (TF) and yellow fever (YF), when administered with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine (MenACWY-CRM). Methods. Healthy adults (18–≤60 years) were randomized to one of three vaccine regimens: TF + YF + MenACWY-CRM (group I; n = 100), TF + YF (group II; n = 101), or MenACWY-CRM (group III; n = 100). Immunogenicity at baseline and 4 weeks post-vaccination (day 29) was assessed by serum bactericidal assay using human complement (hSBA), enzyme-linked immunosorbent assay (ELISA), or a neutralization test. Adverse events (AEs) and serious adverse events (SAEs) were collected throughout the study period. Results. Non-inferiority of post-vaccination geometric mean concentrations (GMCs) and geometric mean titers (GMTs) was established for TF and YF vaccines, respectively, when given concomitantly with MenACWY-CRM vaccine versus when given alone. The percentages of subjects with seroprotective neutralizing titers against YF on day 29 were similar in groups I and II. The antibody responses to meningococcal serogroups A, C, W-135, and Y were within the same range when MenACWY-CRM was given separately or together with TF and YF vaccines. The percentage of subjects reporting AEs was the same for TF and YF vaccines with or without MenACWY-CRM vaccine. There were no reports of SAEs or AEs leading to study withdrawals. Conclusions. These data provide evidence that MenACWY-CRM can be administered with typhoid Vi polysaccharide vaccine and live attenuated YF vaccine without compromising antibody responses stimulated by the individual vaccines. MenACWY-CRM can, therefore, be incorporated into travelers’ vaccination programs without necessitating an additional clinic visit (NCT01466387).
M
eningococcal disease, caused by Neisseria meningitidis is recognized as one of the leading causes of bacterial meningitis and can also cause sepsis and pneumonia. Among the 12 known N. meningitidis serogroups, which differ immunologically because of structural differences in the polysaccharides of their outer capsule,
Corresponding Author: Ashwani Kumar Arora, MD, Novartis Vaccines and Diagnostics S.r.l., Via Fiorentina 1, Siena I-53100, Italy. E-mail: [email protected] © 2014 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2015; Volume 22 (Issue 1): 48–56
six serogroups are considered significant causes of epidemics: A, B, C, W-135, X, and Y.1 – 3 Because of the unpredictability of the epidemiology of the disease, broad protection against as many serogroups as possible and across a wide age range would be optimal to prevent meningococcal disease.4 Meningococcal disease is rarely reported in travelers;5 the estimated incidence in travelers is 0.4 per 100,000 population per year.6 However, with its rapid onset and progression leading to potentially devastating effects, this disease can be a concern, especially for those traveling to areas where medical care
Co-administration of MenACWY, typhoid fever and yellow fever vaccines
is limited.5 Furthermore, international travelers can also facilitate the global spread of meningococcal disease, raising possible public health concerns.5 There are currently three licensed quadrivalent meningococcal conjugate vaccines, differing primarily in the type of carrier protein, that offer protection against N. meningitidis serogroups A, C, W-135, and Y.7 The quadrivalent meningococcal glycoconjugate ACWY-CRM (MenACWY-CRM) conjugated vaccine (Menveo® , Novartis Vaccines and Diagnostics, Siena, Italy) containing the cross-reactive material 197 (CRM197 ), the nontoxic mutant of diphtheria toxin as the conjugation protein, is approved in Europe for active immunization, to prevent invasive meningococcal disease in children from 2 years of age, adolescents, and adults at risk of exposure. In the United States, vaccination with MenACWY-CRM is approved for subjects from 2 months to 55 years of age.8 Results from phase 3 studies have shown that the vaccine is well tolerated and highly immunogenic.9,10 Individuals who are advised to receive vaccination against meningococcal disease include persons traveling to countries in which meningococcal disease is epidemic or hyperendemic, for example, countries in the African sub-Sahara belt or countries where recent outbreaks of meningococcal disease have been reported.11,12 Meningococcal vaccination is required for travelers to Saudi Arabia during the time of the annual religious pilgrimage (the Hajj and Umrah) to Mecca.13 Vaccinations for typhoid fever (TF) and yellow fever (YF) are also commonly recommended for travelers to at-risk areas. TF is a severe and occasionally life-threatening illness caused by the bacterium Salmonella enterica serotype Typhi.14 Pre-travel vaccination for TF is recommended for many destinations around the world including Asia, Africa, and Latin America.15,16 YF is a serious, potentially fatal, viral infection caused by a mosquito-borne flavivirus. YF vaccination is recommended for persons who are traveling to the tropical areas of South America and Africa where YF is endemic.17,18 YF is the only disease specifically designated in the International Health Regulations for which proof of vaccination or prophylaxis is required for travelers as a condition of entry to certain countries.19 – 21 Multiple vaccines are often prescribed in pre-travel consultations, and, therefore, potential interactions between vaccines must be considered. In this report, we present the results of a phase 3b clinical trial that evaluated the immunogenicity and safety of travel vaccines against TF and YF administered with or without MenACWY-CRM vaccine in healthy adults. Materials and Methods Study Design This phase 3b randomized, open-label, multi-center study was conducted in four centers in Germany
49
and one in the Czech Republic between January and April 2012 in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice (Clinicaltrials.gov identifier: NCT01466387). The protocol was approved by the Ethics Review Committee of each participating center. This clinical trial evaluated the immunogenicity and safety of concomitant administration of MenACWY-CRM with travel vaccines for TF, YF, Japanese encephalitis (JE), and rabies, in two different schemes. The primary objective of the study was to establish the non-inferiority of TF and YF vaccines given concomitantly with MenACWY-CRM compared with TF and YF vaccines given alone, as measured by post-vaccination geometric mean concentrations (GMCs) and geometric mean titers (GMTs) for TF and YF, respectively. The secondary objectives were to assess seroprotection rates, elicited by the YF vaccine, with or without concomitant administration of MenACWY-CRM and to assess the antibody responses to MenACWY-CRM when administered concomitantly with TF and YF vaccines or given alone. Seroprotection rates for TF were not evaluated because of the lack of a validated assay. The safety profiles of the vaccines, administered alone or concomitantly, were assessed in terms of the frequency and percentage of all reported adverse events (AEs) and serious adverse events (SAEs). A total of 301 subjects were randomized to one of the three following vaccination groups: group I (TF + YF + MenACWY-CRM; N = 100), group II (TF + YF; N = 101), and group III (MenACWY-CRM; N = 100) (Figure 1). Participants Female and male individuals between 18 and 60 years of age who provided written informed consent were enrolled. Subjects were excluded if they had a history of N. meningitidis infection, TF, rabies, or any flavivirus infection (based on recall, as part of collecting their medical history); had had previous vaccination with study vaccines or antigens related to any of the study vaccines (including any other flavivirus vaccine) within the last 5 years, or had received investigational agents or investigational or licensed vaccines within 30 days prior to enrolment, or expected to receive an investigational agent or vaccine prior to completion of the study; had any serious disease, impairment of immune function, or had had a previous serious vaccine reaction; had a bleeding diathesis, or any condition that may have been associated with a prolonged bleeding time; had experienced a recent acute infection or fever (≥38∘ C), or had received an anti-malaria drug up to 2 months prior to the study; were pregnant or breastfeeding. Concomitant medications that led to exclusion included routine use of inhaled or systemic corticosteroids, any systemic antibiotic treatment, and antiviral therapy or immunosuppressive therapy. J Travel Med 2015; 22: 48–56
50
Alberer et al.
Figure 1 Subject disposition flowchart showing subject numbers, study structure, and reasons for exclusion of subjects. TF = typhoid fever; YF = yellow fever; MenACWY-CRM = quadrivalent meningococcal glycoconjugate ACWY-CRM; PPS = per protocol set; PD = protocol deviation; LTF = lost to follow-up.
Vaccines ®
The MenACWY-CRM vaccine (Menveo , Novartis Vaccines and Diagnostics S.r.l.) was prepared by extemporaneous mixing of the lyophilized MenA component with the liquid MenCWY component. After reconstitution, each 0.5 mL dose contained 10 μg of meningococcal serogroup A and 5 μg each of capsular polysaccharide of serogroups C, W-135, and Y, and 32.7 to 64.1 μg of CRM197 , without adjuvant. The MenACWY-CRM vaccine was administered by intramuscular injection on day 1. A 0.5 mL dose of TF vaccine (Typhim Vi® , Sanofi Pasteur MSD) contained 25 μg purified Vi polysaccharide and was administered by intramuscular injection on day 1. The YF vaccine (Stamaril® , Sanofi Pasteur MSD) powder was reconstituted by adding the provided solvent to the vial followed by subcutaneous injection on day 1. Each 0.5 mL dose contained not less than 1,000 LD50 units YF virus 17 D-204 strain. When participants received two vaccines on the same arm, they were administered at least three centimeters apart from each other. J Travel Med 2015; 22: 48–56
Immunogenicity Assessment Blood samples were obtained before vaccination (day 1) and 4 weeks (day 29) after vaccination. Sera were analyzed using validated methods at the Novartis Clinical Sciences Laboratory, Marburg, Germany (TF and MenACWY-CRM antibody responses), and Focus Diagnostics, Inc., Cypress, CA, USA (YF antibody responses). Antibody responses to TF and YF vaccines were assessed by enzyme-linked immunosorbent assay (ELISA) and a neutralization test, respectively. Antibody titers or concentrations were expressed as GMTs (for YF) or GMCs (for TF). Seroprotection for YF was defined as the percentage of subjects with anti-YF neutralizing antibody titers ≥1/10 on day 29. Seroprotection for TF was not assessed as there is no commercially available assay or validated surrogate marker based on Vi-antibodies that shows protection against TF. Antibody responses against meningococcal serogroups A, C, W-135, and Y were assessed by serum bactericidal assays using human complement (hSBA) and expressed as hSBA GMTs, percentage of subjects
51
Co-administration of MenACWY, typhoid fever and yellow fever vaccines
with seroresponse (for a subject with a baseline hSBA 0.5. Seroresponse rates, GMTs, GMCs, their ratios, percentage of subjects achieving hSBA ≥1 : 8, and corresponding 95% CI were calculated per vaccine group. Antibody titers/concentrations below the limit of detection in all assays were set at half the limit of detection. Safety data were evaluated descriptively, and summarized by the percentage and number of subjects with events in each group. The primary immunogenicity analyses were performed on the per protocol set (PPS), that is, subjects who received all the vaccinations, provided an evaluable serum sample at the relevant time points, and had no protocol deviations. Secondary immunogenicity analyses were performed on the modified intention-to-treat (MITT) Table 1
Of the 301 subjects who were enrolled in this part of the study (Figure 1), 299 completed the study; one subject was lost to follow-up on day 3 and one subject was withdrawn prematurely on day 29 because of protocol deviation (did not satisfy the entry criteria on account of having a medical history of hypercholesterolemia and myocardial infarction and the concomitant use of acetylsalicylic acid, which could have been associated with a prolonged bleeding time, and had no post-vaccination blood draw). Both these subjects were excluded from the immunogenicity analysis (PPS). In addition, two other subjects who completed the study were subsequently also excluded from the PPS because of protocol deviations with regard to the use of concomitant medication (both subjects used corticosteroids) (Figure 1). The baseline demographics of the enrolled subjects are presented in Table 1. Groups were comparable with respect to age, weight, height, and ethnicity.
Immunogenicity Primary Objectives On day 29, the lower bound of the two-sided 95% CI of the ratio of GMCs for TF and ratio of GMTs for YF (group I : group II) were >0.5, when given with and without MenACWY-CRM, demonstrating non-inferiority of the immune response (Table 2). Overall, antibody responses on day 29 were high in both groups, with a 27-fold (group I) and 21-fold (group II) increase in GMCs against TF and a 419-fold (group I) and 576-fold (group II) increase in GMTs against YF, from baseline.
Study population demographics of enrolled subjects
Mean age, years ± SD Male, % Female, % Ethnicity, % White Asian Black or African American Other Mean weight, kg ± SD Mean height, cm ± SD
Group I TF + YF + MenACWY-CRM N = 100
Group II TF + YF N = 101
Group III MenACWY-CRM N = 100
35.1 ± 11.0 56 44
36.5 ± 10.8 51 49
36.9 ± 11.2 50 50
96 1 3 0 78.7 ± 18.1 175.2 ± 9.5
98
ORIGINAL ARTICLE
Safety and Immunogenicity of Typhoid Fever and Yellow Fever Vaccines When Administered Concomitantly With Quadrivalent Meningococcal ACWY Glycoconjugate Vaccine in Healthy Adults Martin Alberer, MD,∗ Gerd Burchard, MD,† Tomas Jelinek, MD,‡ Emil Reisinger, MD,§ Jiri Beran, MD,|| Lucie Cerna Hlavata, MD,¶ Eduardo Forleo-Neto, MD,¶ Alemnew F. Dagnew, MD,¶ and Ashwani K. Arora, MD# of Infectious Diseases and Tropical Medicine, University of Munich, Munich, Germany; † University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ‡ Berlin Center for Travel and Tropical Medicine, Berlin, Germany; § Department of Tropical Medicine and Infectious Diseases, University of Rostock Medical School, Rostock, Germany; || Vaccination and Travel Medicine Centre, Hradec Kralove, Czech Republic; ¶ Novartis Vaccines and Diagnostics Inc., Cambridge, MA, USA; # Novartis Vaccines and Diagnostics S.r.l., Sienna, Italy ∗ Department
DOI: 10.1111/jtm.12164
Background. Compact and short pre-travel immunization schedules, which include several vaccinations in a single visit, are desirable for many travelers. However, concomitant vaccination could potentially compromise immunogenicity and/or safety of the individual vaccines and, therefore, possible vaccine interferences should be carefully assessed. This article discusses the immunogenicity and safety of travel vaccines for typhoid fever (TF) and yellow fever (YF), when administered with or without a quadrivalent meningococcal glycoconjugate ACWY-CRM vaccine (MenACWY-CRM). Methods. Healthy adults (18–≤60 years) were randomized to one of three vaccine regimens: TF + YF + MenACWY-CRM (group I; n = 100), TF + YF (group II; n = 101), or MenACWY-CRM (group III; n = 100). Immunogenicity at baseline and 4 weeks post-vaccination (day 29) was assessed by serum bactericidal assay using human complement (hSBA), enzyme-linked immunosorbent assay (ELISA), or a neutralization test. Adverse events (AEs) and serious adverse events (SAEs) were collected throughout the study period. Results. Non-inferiority of post-vaccination geometric mean concentrations (GMCs) and geometric mean titers (GMTs) was established for TF and YF vaccines, respectively, when given concomitantly with MenACWY-CRM vaccine versus when given alone. The percentages of subjects with seroprotective neutralizing titers against YF on day 29 were similar in groups I and II. The antibody responses to meningococcal serogroups A, C, W-135, and Y were within the same range when MenACWY-CRM was given separately or together with TF and YF vaccines. The percentage of subjects reporting AEs was the same for TF and YF vaccines with or without MenACWY-CRM vaccine. There were no reports of SAEs or AEs leading to study withdrawals. Conclusions. These data provide evidence that MenACWY-CRM can be administered with typhoid Vi polysaccharide vaccine and live attenuated YF vaccine without compromising antibody responses stimulated by the individual vaccines. MenACWY-CRM can, therefore, be incorporated into travelers’ vaccination programs without necessitating an additional clinic visit (NCT01466387).
M
eningococcal disease, caused by Neisseria meningitidis is recognized as one of the leading causes of bacterial meningitis and can also cause sepsis and pneumonia. Among the 12 known N. meningitidis serogroups, which differ immunologically because of structural differences in the polysaccharides of their outer capsule,
Corresponding Author: Ashwani Kumar Arora, MD, Novartis Vaccines and Diagnostics S.r.l., Via Fiorentina 1, Siena I-53100, Italy. E-mail: [email protected] © 2014 International Society of Travel Medicine, 1195-1982 Journal of Travel Medicine 2015; Volume 22 (Issue 1): 48–56
six serogroups are considered significant causes of epidemics: A, B, C, W-135, X, and Y.1 – 3 Because of the unpredictability of the epidemiology of the disease, broad protection against as many serogroups as possible and across a wide age range would be optimal to prevent meningococcal disease.4 Meningococcal disease is rarely reported in travelers;5 the estimated incidence in travelers is 0.4 per 100,000 population per year.6 However, with its rapid onset and progression leading to potentially devastating effects, this disease can be a concern, especially for those traveling to areas where medical care
Co-administration of MenACWY, typhoid fever and yellow fever vaccines
is limited.5 Furthermore, international travelers can also facilitate the global spread of meningococcal disease, raising possible public health concerns.5 There are currently three licensed quadrivalent meningococcal conjugate vaccines, differing primarily in the type of carrier protein, that offer protection against N. meningitidis serogroups A, C, W-135, and Y.7 The quadrivalent meningococcal glycoconjugate ACWY-CRM (MenACWY-CRM) conjugated vaccine (Menveo® , Novartis Vaccines and Diagnostics, Siena, Italy) containing the cross-reactive material 197 (CRM197 ), the nontoxic mutant of diphtheria toxin as the conjugation protein, is approved in Europe for active immunization, to prevent invasive meningococcal disease in children from 2 years of age, adolescents, and adults at risk of exposure. In the United States, vaccination with MenACWY-CRM is approved for subjects from 2 months to 55 years of age.8 Results from phase 3 studies have shown that the vaccine is well tolerated and highly immunogenic.9,10 Individuals who are advised to receive vaccination against meningococcal disease include persons traveling to countries in which meningococcal disease is epidemic or hyperendemic, for example, countries in the African sub-Sahara belt or countries where recent outbreaks of meningococcal disease have been reported.11,12 Meningococcal vaccination is required for travelers to Saudi Arabia during the time of the annual religious pilgrimage (the Hajj and Umrah) to Mecca.13 Vaccinations for typhoid fever (TF) and yellow fever (YF) are also commonly recommended for travelers to at-risk areas. TF is a severe and occasionally life-threatening illness caused by the bacterium Salmonella enterica serotype Typhi.14 Pre-travel vaccination for TF is recommended for many destinations around the world including Asia, Africa, and Latin America.15,16 YF is a serious, potentially fatal, viral infection caused by a mosquito-borne flavivirus. YF vaccination is recommended for persons who are traveling to the tropical areas of South America and Africa where YF is endemic.17,18 YF is the only disease specifically designated in the International Health Regulations for which proof of vaccination or prophylaxis is required for travelers as a condition of entry to certain countries.19 – 21 Multiple vaccines are often prescribed in pre-travel consultations, and, therefore, potential interactions between vaccines must be considered. In this report, we present the results of a phase 3b clinical trial that evaluated the immunogenicity and safety of travel vaccines against TF and YF administered with or without MenACWY-CRM vaccine in healthy adults. Materials and Methods Study Design This phase 3b randomized, open-label, multi-center study was conducted in four centers in Germany
49
and one in the Czech Republic between January and April 2012 in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice (Clinicaltrials.gov identifier: NCT01466387). The protocol was approved by the Ethics Review Committee of each participating center. This clinical trial evaluated the immunogenicity and safety of concomitant administration of MenACWY-CRM with travel vaccines for TF, YF, Japanese encephalitis (JE), and rabies, in two different schemes. The primary objective of the study was to establish the non-inferiority of TF and YF vaccines given concomitantly with MenACWY-CRM compared with TF and YF vaccines given alone, as measured by post-vaccination geometric mean concentrations (GMCs) and geometric mean titers (GMTs) for TF and YF, respectively. The secondary objectives were to assess seroprotection rates, elicited by the YF vaccine, with or without concomitant administration of MenACWY-CRM and to assess the antibody responses to MenACWY-CRM when administered concomitantly with TF and YF vaccines or given alone. Seroprotection rates for TF were not evaluated because of the lack of a validated assay. The safety profiles of the vaccines, administered alone or concomitantly, were assessed in terms of the frequency and percentage of all reported adverse events (AEs) and serious adverse events (SAEs). A total of 301 subjects were randomized to one of the three following vaccination groups: group I (TF + YF + MenACWY-CRM; N = 100), group II (TF + YF; N = 101), and group III (MenACWY-CRM; N = 100) (Figure 1). Participants Female and male individuals between 18 and 60 years of age who provided written informed consent were enrolled. Subjects were excluded if they had a history of N. meningitidis infection, TF, rabies, or any flavivirus infection (based on recall, as part of collecting their medical history); had had previous vaccination with study vaccines or antigens related to any of the study vaccines (including any other flavivirus vaccine) within the last 5 years, or had received investigational agents or investigational or licensed vaccines within 30 days prior to enrolment, or expected to receive an investigational agent or vaccine prior to completion of the study; had any serious disease, impairment of immune function, or had had a previous serious vaccine reaction; had a bleeding diathesis, or any condition that may have been associated with a prolonged bleeding time; had experienced a recent acute infection or fever (≥38∘ C), or had received an anti-malaria drug up to 2 months prior to the study; were pregnant or breastfeeding. Concomitant medications that led to exclusion included routine use of inhaled or systemic corticosteroids, any systemic antibiotic treatment, and antiviral therapy or immunosuppressive therapy. J Travel Med 2015; 22: 48–56
50
Alberer et al.
Figure 1 Subject disposition flowchart showing subject numbers, study structure, and reasons for exclusion of subjects. TF = typhoid fever; YF = yellow fever; MenACWY-CRM = quadrivalent meningococcal glycoconjugate ACWY-CRM; PPS = per protocol set; PD = protocol deviation; LTF = lost to follow-up.
Vaccines ®
The MenACWY-CRM vaccine (Menveo , Novartis Vaccines and Diagnostics S.r.l.) was prepared by extemporaneous mixing of the lyophilized MenA component with the liquid MenCWY component. After reconstitution, each 0.5 mL dose contained 10 μg of meningococcal serogroup A and 5 μg each of capsular polysaccharide of serogroups C, W-135, and Y, and 32.7 to 64.1 μg of CRM197 , without adjuvant. The MenACWY-CRM vaccine was administered by intramuscular injection on day 1. A 0.5 mL dose of TF vaccine (Typhim Vi® , Sanofi Pasteur MSD) contained 25 μg purified Vi polysaccharide and was administered by intramuscular injection on day 1. The YF vaccine (Stamaril® , Sanofi Pasteur MSD) powder was reconstituted by adding the provided solvent to the vial followed by subcutaneous injection on day 1. Each 0.5 mL dose contained not less than 1,000 LD50 units YF virus 17 D-204 strain. When participants received two vaccines on the same arm, they were administered at least three centimeters apart from each other. J Travel Med 2015; 22: 48–56
Immunogenicity Assessment Blood samples were obtained before vaccination (day 1) and 4 weeks (day 29) after vaccination. Sera were analyzed using validated methods at the Novartis Clinical Sciences Laboratory, Marburg, Germany (TF and MenACWY-CRM antibody responses), and Focus Diagnostics, Inc., Cypress, CA, USA (YF antibody responses). Antibody responses to TF and YF vaccines were assessed by enzyme-linked immunosorbent assay (ELISA) and a neutralization test, respectively. Antibody titers or concentrations were expressed as GMTs (for YF) or GMCs (for TF). Seroprotection for YF was defined as the percentage of subjects with anti-YF neutralizing antibody titers ≥1/10 on day 29. Seroprotection for TF was not assessed as there is no commercially available assay or validated surrogate marker based on Vi-antibodies that shows protection against TF. Antibody responses against meningococcal serogroups A, C, W-135, and Y were assessed by serum bactericidal assays using human complement (hSBA) and expressed as hSBA GMTs, percentage of subjects
51
Co-administration of MenACWY, typhoid fever and yellow fever vaccines
with seroresponse (for a subject with a baseline hSBA 0.5. Seroresponse rates, GMTs, GMCs, their ratios, percentage of subjects achieving hSBA ≥1 : 8, and corresponding 95% CI were calculated per vaccine group. Antibody titers/concentrations below the limit of detection in all assays were set at half the limit of detection. Safety data were evaluated descriptively, and summarized by the percentage and number of subjects with events in each group. The primary immunogenicity analyses were performed on the per protocol set (PPS), that is, subjects who received all the vaccinations, provided an evaluable serum sample at the relevant time points, and had no protocol deviations. Secondary immunogenicity analyses were performed on the modified intention-to-treat (MITT) Table 1
Of the 301 subjects who were enrolled in this part of the study (Figure 1), 299 completed the study; one subject was lost to follow-up on day 3 and one subject was withdrawn prematurely on day 29 because of protocol deviation (did not satisfy the entry criteria on account of having a medical history of hypercholesterolemia and myocardial infarction and the concomitant use of acetylsalicylic acid, which could have been associated with a prolonged bleeding time, and had no post-vaccination blood draw). Both these subjects were excluded from the immunogenicity analysis (PPS). In addition, two other subjects who completed the study were subsequently also excluded from the PPS because of protocol deviations with regard to the use of concomitant medication (both subjects used corticosteroids) (Figure 1). The baseline demographics of the enrolled subjects are presented in Table 1. Groups were comparable with respect to age, weight, height, and ethnicity.
Immunogenicity Primary Objectives On day 29, the lower bound of the two-sided 95% CI of the ratio of GMCs for TF and ratio of GMTs for YF (group I : group II) were >0.5, when given with and without MenACWY-CRM, demonstrating non-inferiority of the immune response (Table 2). Overall, antibody responses on day 29 were high in both groups, with a 27-fold (group I) and 21-fold (group II) increase in GMCs against TF and a 419-fold (group I) and 576-fold (group II) increase in GMTs against YF, from baseline.
Study population demographics of enrolled subjects
Mean age, years ± SD Male, % Female, % Ethnicity, % White Asian Black or African American Other Mean weight, kg ± SD Mean height, cm ± SD
Group I TF + YF + MenACWY-CRM N = 100
Group II TF + YF N = 101
Group III MenACWY-CRM N = 100
35.1 ± 11.0 56 44
36.5 ± 10.8 51 49
36.9 ± 11.2 50 50
96 1 3 0 78.7 ± 18.1 175.2 ± 9.5
98
