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Introduction:Mozambique is one of the poorest nations in the world and its health budget is heavily dependent on external funding. Increasingly, donors prefer to direct their funds through international non-governmental organizations instead of direct donations to the State budget. In the current climate of increased emphasis on health system strengthening, a strong and stable partnership between government and international non-governmental organizations is pivotal for health system strengthening in Mozambique. Methods:the study evaluates the current partnership through a standardized survey to healthcare workers employed by international non-governmental organizations in health (INGO, private) and the ministry of health (MOH, public). Results of the survey have been analyzed only descriptively and no statistical evaluations have been performed. Results:out of the valid 109 responses obtained 55.1% were from MOH cadres and 45.0% from INGO cadres. Most have been in the health sector for more than 5 years. Most of the respondents recognize that INGOs assist the government in strengthening the health system (71.6%), see the internal brain drain to INGOs and salary scale difference as major problems (70.6% and 78.0%); 87.2% reported that the coordination between INGOs and government needs to be improved. MOH cadres perceived the migration of cadres to INGOs and the need for improving coordination as major issues more acutely than their INGO counterparts (80.0% vs. 59.2% and 88.3% vs. 85.7% respectively). INGOs were perceived to offer better quality health services by 51.4% of respondents (of these 69.4% were INGO respondents). The quality of health services was alike between INGOs and MOH for 33% of the respondents. Conclusion:through the various efforts outlined the MOH and INGOs are moving towards an environment of mutual accountability, joint planning and coordination as well as harmonization of activities; but there are still challenges to be addressed. Prioritization and increased funding of the planning unit and planning and cooperation directorate as well as strategies for workforce retention are urgently needed.

Shigella is the second most deadly diarrheal disease among children under five years of age, after rotavirus, with high morbidity and mortality in developing countries. Currently, no vaccine is widely available, and the increasing levels of multidrug resistance make Shigella a high priority for vaccine development. The single-component candidate vaccine against Shigella sonnei (1790GAHB), developed using the GMMA technology, contains the O antigen (OAg) portion of lipopolysaccharide (LPS) as active moiety. The vaccine was well tolerated and immunogenic in early-phase clinical trials. In a phase 1 placebo-controlled dose escalation trial in France (NCT02017899), three doses of five different vaccine formulations (0.06/1, 0.3/5, 1.5/25, 3/50, 6/100 µg of OAg/protein) were administered to healthy adults. In the phase 1 extension trial (NCT03089879), conducted 2–3 years following the parent study, primed individuals who had undetectable antibody levels before the primary series received a 1790GAHB booster dose (1.5/25 µg OAg/protein). Controls were unprimed participants immunized with one 1790GAHB dose. The current analysis assessed the functionality of sera collected from both studies using a high-throughput luminescence-based serum bactericidal activity (SBA) assay optimized for testing human sera. Antibodies with complement-mediated bactericidal activity were detected in vaccinees but not in placebo recipients. SBA titers increased with OAg dose, with a persistent response up to six months after the primary vaccination with at least 1.5/25 µg of OAg/protein. The booster dose induced a strong increase of SBA titers in most primed participants. Correlation between SBA titers and anti-S. sonnei LPS serum immunoglobulin G levels was observed. Results suggest that GMMA is a promising OAg delivery system for the generation of functional antibody responses and persistent immunological memory.

Summary Background Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults. Methods To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France (“study 1”) and the United Kingdom (“study 2”) between February 2014 and April 2015 (ClinicalTrials.gov, number NCT02017899 and NCT02034500, respectively) in 18–45 years old subjects (50 in study 1, 52 in study 2). Increasing doses of Alhydrogel adsorbed 1790, expressed by both O Antigen (OAg) and protein quantity, or placebo were given either by intramuscular route (0.059/1, 0.29/5, 1.5/25, 2.9/50, 5.9/100 μg of OAg/μg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10 μg ID, 0.29/5, 1.2/20, 4.8/80 μg IN and 0.29/5 μg IM, respectively; study 2). In absence of serologic correlates of protection for Shigella sonnei, vaccine induced immunogenicity was compared to anti-LPS antibody in a population naturally exposed to S. sonnei. Findings Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses ≥ 1.5/25 μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. No vaccine group in study 2 achieved median antibody greater than the median convalescent antibody. Interpretation Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100 μg and induces antibody to the OAg of at least the same magnitude of those observed following natural exposure to the pathogen. Vaccine administered by ID or IN, although well tolerated, is poorly immunogenic at the doses delivered. The data support the use of the GMMA technology for the development of intramuscular multivalent Shigella vaccines., Highlights • GVGH GMMA vaccine against S. sonnei was well tolerated by IM, IN and ID routes of immunization in young European adults. • Doses ≥ 1.5/25 μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. • Clinical data support the use of the GMMA technology for the development of intramuscular Shigella multivalent vaccines. Shigellosis is an important cause of diarrhoea especially in children of developing countries. No vaccine is available. Based on the 2015 Global Burden of Disease, Shigella caused approximately 164,000 deaths due to diarrhoea in 2015, supporting the public health relevance of the disease and the need for a vaccine. The GMMA (Generalized Modules for Membrane Antigens) technology was used for the development of a vaccine against Shigella sonnei which, tested in these trials for the first time, was shown to be well tolerated in young adults and induced specific antibody titres at least as high as after natural infection.

The investigational Shigella sonnei vaccine (1790GAHB) based on GMMA (generalized modules for membrane antigens) is immunogenic, with an acceptable safety profile in adults. However, pre-vaccination anti-S. sonnei lipopolysaccharide (LPS) antibody levels seemed to impact vaccine-related immune responses. This phase 1, open-label, non-randomized extension study (ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT03089879","term_id":"NCT03089879"}}NCT03089879) evaluated immunogenicity of a 1790GAHB booster dose in seven adults with undetectable antibodies prior to priming with three 1790GAHB vaccinations 2–3 years earlier (boosted group), compared to one dose in 28 vaccine-naive individuals (vaccine-naive group). Anti-S. sonnei LPS serum IgG geometric mean concentrations and seroresponse (increase of ≥25 EU or ≥50% from baseline antibody ≤ 50 EU and ≥50 EU, respectively) rates were calculated at vaccination (day [D]1), D8, D15, D29, D85. Safety was assessed. Geometric mean concentrations at D8 were 168 EU (boosted group) and 32 EU (vaccine-naive group). Response peaked at D15 (883 EU) and D29 (100 EU) for the boosted and vaccine-naive groups. Seroresponse rates at D8 were 86% (boosted group) and 24% (vaccine-naive group) and increased at subsequent time points. Across both groups, pain (local) and fatigue (systemic) were the most frequent solicited adverse events (AEs). Unsolicited AEs were reported by 57% of boosted and 25% of vaccine-naive participants. No deaths, serious AEs, or AEs of special interest (except one mild neutropenia case, possibly vaccination-related) were reported. One 1790GAHB dose induced a significant booster response in previously-primed adults, regardless of priming dose, and strong immune response in vaccine-naive individuals. Vaccination was well tolerated.

Background. Mass vaccination campaigns of the population aged 1–29 years with 1 dose of group A meningococcal (MenA) conjugate vaccine (PsA-TT, MenAfriVac) in African meningitis belt countries has resulted in the near-disappearance of MenA. The vaccine was tested in clinical trials in Africa and in India and found to be safe and highly immunogenic compared with the group A component of the licensed quadrivalent polysaccharide vaccine (PsACWY). Antibody persistence in Africa and in India was investigated. Methods. A total of 900 subjects aged 2–29 years were followed up for 4 years in Senegal, Mali, and The Gambia (study A). A total of 340 subjects aged 2–10 years were followed up for 1 year in India (study B). In study A, subjects were randomized in a 2:1 ratio, and in study B a 1:1 ratio to receive either PsA-TT or PsACWY. Immunogenicity was evaluated by measuring MenA serum bactericidal antibody (SBA) with rabbit complement and by a group A–specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay. Results. In both studies, substantial SBA decay was observed at 6 months postvaccination in both vaccine groups, although more marked in the PsACWY group. At 1 year and 4 years (only for study A) postvaccination, SBA titers were relatively sustained in the PsA-TT group, whereas a slight increasing trend, more pronounced among the youngest, was observed in the participants aged

Summary Background Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM 197 ) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM 197 in participants of various ages in endemic countries in south and southeast Asia. Methods We did two randomised, observer-blind, age de-escalation, phase 2 trials at two sites in Pakistan and India (study A), and at one site in the Philippines (study B), between March 2, 2011, and Aug 9, 2012. Adults aged 18–45 years, children aged 24–59 months, older infants aged 9–12 months, and infants aged 6–8 weeks were randomly assigned (1:1) with a computer-generated randomisation list (block size of four) to receive either 5 μg Vi-CRM 197 or 25 μg Vi-polysaccharide vaccine (or 13-valent pneumococcal conjugate vaccine in children younger than 2 years). Both infant populations received Vi-CRM 197 concomitantly with vaccines of the Expanded Programme on Immunization (EPI), according to WHO schedule. With the exception of designated study site personnel responsible for vaccine preparation, study investigators, those assessing outcomes, and data analysts were masked to treatment allocation. We specified no a-priori null hypothesis for the immunogenicity or safety objectives and all analyses were descriptive. Analyses were by modified intention-to-treat. These studies are registered with ClinicalTrials.gov, numbers NCT01229176 and NCT01437267. Findings 320 participants were enrolled and vaccinated in the two trials: 200 in study A (all age groups) and 120 in study B (children and infants only), of whom 317 (99%) were included in the modified intention-to-treat analysis. One dose of Vi-CRM 197 significantly increased concentrations of anti-Vi antibody in adults (from 113 U/mL [95% CI 67–190] to 208 U/mL [117–369]), children (201 U/mL [138–294] to 368 U/mL [234–580]), and older infants (179 U/mL [129–250] to 249 U/mL [130–477]). However, in children and older infants, a second dose of conjugate vaccine had no incremental effect on antibody titres and, at all ages, concentrations of antibodies increased substantially 6 months after vaccination (from 55 U/mL [33–94] to 63 U/mL [35–114] in adults, from 23 U/mL [15–34] to 51 U/mL [34–76] in children, and from 21 U/mL [14–31] to 22 U/mL [14–33] in older infants). Immune response in infants aged 6–8 weeks was lower than that in older participants and, 6 months after third vaccination, antibody concentrations were significantly higher than pre-vaccination concentrations in Filipino (21 U/mL [16–28] vs 2·88 U/mL [1·95–4·25]), but not Pakistani (3·76 U/mL [2·77–5·08] vs 2·77 U/mL [2·1–3·66]), infants. Vi-CRM 197 was safe and well tolerated and did not induce any significant interference with EPI vaccines. No deaths or vaccine-related serious adverse events were reported throughout the studies. Interpretation Vi-CRM 197 is safe and immunogenic in endemic populations of all ages. Given at 9 months of age, concomitantly with measles vaccine, Vi-CRM 197 shows a promise for potential inclusion in EPI schedules of countries endemic for typhoid. An apparent absence of booster response and a reduction in antibody titres 6 months after immunisation should be further investigated, but data show that an immunogenic typhoid vaccine can be safely delivered to infants during EPI visits recommended by WHO. Funding Sclavo Vaccines Association and Regione Toscana.

Background Group A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed. Methods We conducted two studies in Africa to evaluate a new MenA conjugate vaccine (PsA-TT). In study A, 601 children, 12 to 23 months of age, were randomly assigned to receive PsA-TT, a quadrivalent polysaccharide reference vaccine (PsACWY), or a control vaccine (Haemophilus influenzae type b conjugate vaccine [Hib-TT]). Ten months later, these children underwent another round of randomization within each group to receive a full dose of PsA-TT, a one-fifth dose of PsACWY, or a full dose of Hib-TT, with 589 of the original participants receiving a booster dose. In study B, 900 subjects between 2 and 29 years of age were randomly assigned to receive PsA-TT or PsACWY. Safety and reactogenicity were evaluated, and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing an IgG group A-specific enzyme-linked immunosorbent assay. Results In study A, 96.0% of the subjects in the PsA-TT group and 63.7% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline; in study B, 78.2% of the subjects in the PsA-TT group and 46.2% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline. The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3, respectively, than they were in the PsACWY groups (P

The “meningitis belt” of sub-Saharan Africa runs across the continent from Senegal to Ethiopia, and this region is prone to major epidemics of meningococcal meningitis, with a high case fatality rate and serious sequelae. Until recently, most epidemics were due to group A Neisseria meningitidis (MenA). The observed reduction in meningococcal meningitis due to MenA has been due to the development of an affordable group A meningococcal vaccine, PsA-TT (MenAfriVac, Serum Institute of India, Ltd). The Meningitis Vaccine Project, a partnership between the World Health Organization (WHO) and PATH, coordinated the development, testing, licensure, and introduction of this vaccine with the aim of eliminating epidemic meningitis attributable to MenA [1–4]. Since 2010, PsA-TT has been introduced into countries across the meningitis belt through mass campaigns [5, 6]. PsA-TT is expected to confer both longer-lasting individual protection and herd protection than MenA polysaccharide vaccines. Ongoing surveillance shows that no cases of MenA meningococcal disease have occurred in vaccinated individuals [6], but the longevity of this protective immune response is not known. Prior to the introduction of PsA-TT into the African countries of the meningitis belt, multiple clinical trials assessed the safety and immunogenicity of PsA-TT. A trial conducted in children aged 12–23 months demonstrated that this vaccine was immunogenic and induced immune memory. However, antibody persistence is key in maintaining direct and indirect protection [7, 8]. We report here on the persistence of MenA-specific antibodies in individuals vaccinated with PsA-TT in early childhood.

Background. The group A meningococcal vaccine (PsA-TT) clinical development plan included clinical trials in India and in the West African region between 2005 and 2013. During this period, the Meningitis Vaccine Project (MVP) accumulated substantial experience in the ethical conduct of research to the highest standards. Methods. Because of the public–private nature of the sponsorship of these trials and the extensive international collaboration with partners from a diverse setting of countries, the ethical review process was complex and required strategic, timely, and attentive communication to ensure the smooth review and approval for the clinical studies. Investigators and their site teams fostered strong community relationships prior to, during, and after the studies to ensure the involvement and the ownership of the research by the participating populations. As the clinical work proceeded, investigators and sponsors responded to specific questions of informed consent, pregnancy testing, healthcare, disease prevention, and posttrial access. Results. Key factors that led to success included (1) constant dialogue between partners to explore and answer all ethical questions; (2) alertness and preparedness for emerging ethical questions during the research and in the context of evolving international ethics standards; and (3) care to assure that approaches were acceptable in the diverse community contexts. Conclusions. Many of the ethical issues encountered during the PsA-TT clinical development are familiar to groups conducting field trials in different cultural settings. The successful approaches used by the MVP clinical team offer useful examples of how these problems were resolved. Clinical Trials Registration. ISRCTN17662153 (PsA-TT-001); ISRTCN78147026 (PsA-TT-002); ISRCTN87739946 (PsA-TT-003); ISRCTN46335400 (PsA-TT-003a); ISRCTN82484612 (PsA-TT-004); CTRI/2009/091/000368 (PsA-TT-005); PACTR ATMR2010030001913177 (PsA-TT-006); PACTR201110000328305 (PsA-TT-007).

Clinical Infectious Diseases, 61, ISSN:1058-4838, ISSN:1537-6591

This study compares the immunogenicity and safety of a single dose of a new meningococcal A conjugate vaccine (PsA-TT, MenAfriVac™, Serum Institute of India Ltd., Pune) against the meningococcal group A component of a licensed quadrivalent meningococcal polysaccharide vaccine (PsACWY, Mencevax ACWY(®), GSK, Belgium) 28 days after vaccination in Indian children. This double-blind, randomized, controlled study included 340 Indian children aged 2-10 years enrolled from August to October 2007; 169 children received a dose of PsA-TT while 171 children received a dose of PsACWY. Intention-to-treat analysis showed that 95.2% of children in PsA-TT group had a ≥4-fold response in serum bactericidal titers (rSBA) 28 days post vaccination as compared to 78.2% in the PsACWY group. A significantly higher rSBA GMT (11,209, 95%CI 9708-12,942) was noted in the PsA-TT group when compared to PsACWY group (2838, 95%CI 2368-3401). Almost all children in both vaccine groups had a ≥4-fold response in group A-specific IgG concentration but the IgG GMC was significantly greater in the PsA-TT group (89.1 μg/ml, 95%CI 75.5-105.0) when compared to the PsACWY group (15.3 μg/ml, 95%CI 12.3-19.2). Local and systemic reactions during the 4 days after immunization were similar for both vaccine groups except for tenderness (30.2% in PsA-TT group vs 12.3% in PsACWY group). None of the adverse events or serious adverse events was related to the study vaccines. We conclude that MenAfriVac™ is well tolerated and significantly more immunogenic when compared to a licensed polysaccharide vaccine, in 2-to-10-year-old Indian children.

A phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects receiving either investigational meningococcal group A conjugate (PsA-TT), meningococcal ACWY polysaccharide (PsACWY), or Haemophilus influenzae type b (Hib-TT) vaccine. Ten months following vaccination, the 3 study groups were further randomized to receive a dose of PsA-TT, a 1/5 dose of PsACWY, or a dose of Hib-TT vaccine. Group A serum bactericidal antibody (SBA) results have been reported previously, with PsA-TT demonstrating superior immunogenicity versus PsACWY vaccine. Immunogenicity for serogroups W135 and C was assessed by SBA assay to investigate the impact of multiple doses in this age group. Blood samples were taken prior to vaccination, 28 days and 40 weeks post-primary vaccination, and 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY. Subjects who had previously received a full dose of PsACWY had W135 SBA geometric mean titers (GMTs) of 26.1 and 4.4 at 7 and 28 days post-booster vaccination with a 1/5 PsACWY dose, respectively, whereas the W135 SBA GMTs of naive subjects at these time points following vaccination with a 1/5 dose of PsACWY were 861.1 and 14.6, respectively. Similar differences were observed for serogroup C, with SBA GMTs of 99 and 5.9 at 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY, respectively, for naive subjects, compared to 4.1 and 3.2 for previously vaccinated subjects. Immunologic hyporesponsiveness for groups C and W135 was observed following a full dose of PsACWY vaccine at 12 to 23 months of age and a 1/5 dose of PsACWY 10 months later compared to the case for PsACWY-naive subjects receiving a 1/5 dose of PsACWY vaccine. Outbreaks of Neisseria meningitidis group A recur frequently in the African meningitis belt, where they are responsible for high mortality and morbidity. Polysaccharide vaccines against group A have been available since the 1970s, but due to the limitations of these vaccines, polysaccharide-protein conjugate vaccines have been developed. In 2001, the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization (WHO) and the Program for Appropriate Technology in Health (PATH), was created through core funding from the Bill & Melinda Gates Foundation, with the goal of eliminating group A meningococcal epidemics in sub-Saharan Africa through the development and use of a monovalent group A meningococcal conjugate vaccine. A phase I clinical study of a group A meningococcal conjugate vaccine, MenAfriVac

Background: Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM197 in European adults. Methodology: Following randomized blinded comparison of single vaccination with either Vi-CRM197 or licensed polysaccharide vaccines (both containing 25•0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM197 (1•25 µg, 5•0 µg and 12•5 µg of Vi antigen) with the polysaccharide vaccine. These studies are registered with ClinicalTrials.gov, number NCT01123941 and NCT01193907. Principal Findings: All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM197 induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM197 formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship. Conclusions: Vi-CRM197 did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.

A double-blind, randomized, controlled phase I study to assess the safety, immunogenicity, and antibody persistence of a new group A conjugate vaccine (PsA-TT) in volunteers aged 18 to 35 years was previously performed. Subjects received one dose of either the PsA-TT conjugate vaccine, meningococcal A/C polysaccharide vaccine (PsA/C), or tetanus toxoid vaccine. The conjugate vaccine was shown to be safe and immunogenic as demonstrated by a standardized group A-specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and by a serum bactericidal antibody (SBA) assay using rabbit complement (rSBA). This report details further analysis of the sera using four additional immunologic assays to investigate the relationship between the different immunoassays. The immunoassays used were an SBA assay that used human complement (hSBA), a group A-specific IgG multiplexed bead assay, and two opsonophagocytic antibody (OPA) assays which used two different methodologies. For each vaccine group, geometric mean concentrations or geometric mean titers were determined for all assays before and 4, 24, and 48 weeks after vaccination. Pearson’s correlation coefficients were used to assess the relationship between the six assays using data from all available visits. An excellent correlation was observed between the group A-specific IgG concentrations obtained by ELISA and those obtained by the multiplexed bead assay. hSBA and rSBA titers correlated moderately, although proportions of subjects with putatively protective titers and those demonstrating a >4-fold rise were similar. The two OPA methods correlated weakly and achieved only a low correlation with the other immunoassays. The correlation between hSBA and group A-specific IgG was higher for the PsA-TT group than for the PsA/C group. Within the African meningitis belt, unpredictable epidemics of meningococcal disease continue to occur every 5 to 15 years. To prevent these epidemics, a novel serogroup A conjugate meningococcal vaccine was developed. The Meningitis Vaccine Project, a partnership between the World Health Organization (WHO) and PATH (Seattle, WA) with core funding from the Bill and Melinda Gates Foundation, was created in 2001 with the goal of eliminating meningococcal epidemics in sub-Saharan Africa through the development, testing and licensure, and widespread use of serogroup A meningococcal conjugate vaccines (11) (http://www.meningvax.org). A group A meningococcal conjugate vaccine using tetanus toxoid as a carrier protein (PsA-TT) was developed at the Serum Institute of India Ltd., using a new licensed conjugation technique from the Center for Biologics Evaluation

Objective: The present study was carried out to evaluate the safety and immunogenicity of the Haemophilus influenzae type b-CRM 1 9 7 (Hib-CRM 1 9 7 ) conjugate vaccine in relation to the change of adjuvant from aluminum hydroxide to aluminum phosphate (AlPO 4 ). Methods: The present study was a clinical phase II, observer-blind, randomized, multicenter, controlled study. Subjects were healthy infants aged 6-12 weeks, eligible for expanded program of immunization (EPI) routine vaccination and admitted to Hacettepe University Department of Social Pediatrics and Giilveren Health Center, Ankara. A total of 520 healthy infants were randomized in a 2:2:1 ratio to receive at either Chiron Hib/AlPO 4 vaccine or VaxemHib (aluminum hydroxide adjuvant) vaccine or HibTiter (no adjuvant). Vaccines were administered simultaneously with routine diphtheria, tetanus and pertussis (DTaP) and oral polio vaccine (OPV) vaccines at 2, 4 and 6 months of age. Blood samples for anti-plain polysaccharide (PRP) antibody measurement were collected before the first vaccination and 1 month after the last vaccination. After each vaccination parents filled out a diary for 7 days. Results: Out of 520 subjects enrolled, 514 received three doses and were included for safety analysis. Local and systemic reactions occurred with low and similar frequencies in all groups. Only erythema was more common in Chiron Hib/AlPO 4 vaccine (19, 10, 11% in Chiron Hib/AlPO 4 , VaxemHib and HibTiter, respectively, P < 0.05). Nine serious adverse events were reported in seven cases of which none were related to vaccines. A total of 504 subjects were included in the immunogenicity analysis. The three vaccines were highly immunogenic and equivalent in terms of percentage of acquisition of long-term protective levels. The anti-PRP geometric mean titers were 9.9, 8.3 and 5.14 pg/mL, respectively (P < 0.05). Conclusions: The use of aluminum compounds adjuvants in Hib-CRM 1 9 7 conjugate vaccines does not impact the safety profile, while it does increase the magnitude of anti-PRP antibody titers.