A Phase 2/3 double blinded, randomized, placebo-controlled study in healthy adult participants in Vietnam to examine the safety and immunogenicity of an inactivated whole virion, alum adjuvanted, A(H5N1) influenza vaccine (IVACFLU-A/H5N1).

BACKGROUND: A global shortfall of vaccines for avian influenza A(H5N1) would occur, especially in low- and-middle income countries, if a pandemic were to occur. To address this issue, development of a pre-pandemic influenza vaccine was initiated in 2012, leveraging a recently established influenza vaccine manufacturing capacity in Vietnam. METHODS: This was a Phase 2/3, double-blinded, randomized, placebo-controlled study to test the safety and immunogenicity of IVACFLU-A/H5N1 vaccine in healthy adults. Phase 2 was a dose selection study, in which 300 participants were randomized to one of the three groups (15 mcg, 30 mcg, or placebo). Safety and immunogenicity were assessed in all participants. In Phase 3, 630 participants were randomized to receive the IVACFLU-A/H5N1 vaccine dose selected in Phase 2 (15 mcg, n = 525) or placebo (n = 105). Safety was assessed in all Phase 3 participants and immunogenicity was measured in a subset of participants. RESULTS: The vaccine was well tolerated and most of the adverse events were mild and of short duration. Mild pain at the injection site was the most common adverse event seen in 60 percent of participants in the vaccine group in Phase 3. In Phase 2, both 15 mcg and 30 mcg doses were immunogenic, so the lower dose was selected for further testing in Phase 3. In Phase 3 overall seroconversion rates were 68 percent for hemagglutination inhibition (HI), 51 percent for microneutralization (MN) and 56 percent for single radial hemolysis (SRH). The seroprotection rates were 44 percent for HI, 41 percent for MN and 55 percent for SRH. The GMT ratio was 5.31 and 3.7 for HI and MN respectively; GMA was 4.75 for the SRH. CONCLUSION: The IVACFLU A/H5N1 was safe and immunogenic. Development of this pandemic avian influenza vaccine is a welcome addition to the limited global pool of these vaccines. ClinicalTrials.gov register NCT02612909.

A phase 2/3 double-blind, randomized, placebo-controlled study to evaluate the safety and immunogenicity of a seasonal trivalent inactivated split-virion influenza vaccine (IVACFLU-S) in healthy adults in Vietnam.

Background: Under the WHO's Global Action Plan for influenza vaccines, we conducted a phase 2-3 study of IVACFLU-S, a trivalent, seasonal inactivated influenza vaccine candidate.Methods: In the phase 2 portion of the study, 252 participants received one dose of 15 mcg hemagglutinin (HA) vaccine per strain or placebo. Following determination of safety, 636 additional participants were randomized in phase 3 to receive vaccine or placebo. Immunogenicity was assessed in a subset of the participants in the phase 3 study.Results: Higher proportion (70%) of participants in the IVACFLU-S arm reported solicited local adverse events (AEs) (p < .0001) as compared to placebo (25%). Mild injection site pain and tenderness were most common AEs seen in 55% and 60% of participants in the vaccine group. The solicited systemic AEs were comparable (p = .4149). The majority of solicited and unsolicited AEs were mild to moderate in severity. In the vaccine arm for the combined age group of 18-60 years of age, seroconversion against antigens A/H1N1, A/H3N2, and B was achieved in 70.3%, 76.1%, and 54.1% of participants respectively; seroprotection against antigens A/H1N1, A/H3N2, and B was achieved in 83.3%, 86.6%, and 60.3% of participants respectively; and the geometric mean fold rise for the hemagglutinin-inhibition (HI) antibody titers against antigen A/H1N1, A/H3N2, and B were 13.15, 11.85, and 5.87, respectively.Conclusion: This study demonstrates the local reactogenicity, other safety, and immunogenicity of IVACFLU-S, first domestically produced influenza vaccine in Vietnam.ClinicalTrials.gov number NCT03095599 (March 29, 2017).

Safety and immunogenicity of inactivated monovalent influenza A/H1N1 vaccine candidate manufactured in Vietnam.

We tested a new A/H1N1 inactivated influenza vaccine (IIV) manufactured by Institute of Vaccines and Medical Biologics (IVAC), Vietnam in 48 adults in a Phase 1, double-blinded, randomized, placebo-controlled trial. Two doses of unadjuvanted vaccine or placebo were administered three weeks apart. The vaccine was well tolerated with only transient mild local reactions and low-grade fever in a small proportion of the subjects. One serious adverse event considered unrelated to the study product was reported. The IVAC vaccine proved to be highly immunogenic with 91 percent (95% CI: 0.78, 1) of the subjects developing a ≥4 fold immune responses by hemagglutination inhibition (HAI) assay, and 96 percent (95% CI: 0.78, 1) by the microneutralization (MN) assay. Post-vaccination geometric mean titers (GMTs) were 283.7 (95% CI: 161.7, 497.5) in the HAI and 725.7 (95% CI: 411.3, 1280.3) in the MN assay. These promising results merit further development of the vaccine. ClinicalTrials.gov number: NCT01507779.

Randomized safety and immunogenicity trial of a seasonal trivalent inactivated split virion influenza vaccine (IVACFLU-S) in healthy young Vietnamese adults.

BACKGROUND: Under the auspices of the World Health Organization (WHO) Global Action Plan, PATH supported evaluation of a trivalent, seasonal inactivated influenza vaccine candidate produced by the Institute of Vaccines and Medical Biologicals (IVAC), a Vietnamese manufacturer. METHODS: In 2015, 60 healthy adult subjects 18-45years of age were enrolled in a Phase 1, single center, double blind, randomized, placebo-controlled study conducted at a district health center in Thai Binh Province, Vietnam. The study evaluated the overall safety and immunogenicity of a seasonal, trivalent inactivated split virion influenza vaccine. Volunteers were given either vaccine or placebo in a randomized 1:1 ratio. After undergoing screening, eligible volunteers provided their signed consent and were enrolled in the study. On the first day of immunization, randomly chosen volunteers received IVACFLU-S 15µg (mcg) hemagglutinin of each of the three strains in 0.5mL or placebo by intramuscular injection. All volunteers were monitored for adverse events and underwent blood testing at screening and Day 8 to assess the vaccine candidate's safety. Sera obtained before and 21days after immunization were tested for influenza antibody titers using the hemagglutination-inhibition (HAI) and microneutralization tests (MNT). RESULTS: Vaccine was well tolerated, and there were no serious adverse events reported. HAI and MNT identified serum antibody responses against the three influenza strains in nearly all volunteers who received the vaccine. Overall, serum HAI responses of fourfold or greater were observed in 93 percent, 83 percent, and 77 percent of H1, H3, and B strains, respectively. Seroprotection rates were also very high. CONCLUSIONS: IVAC's seasonal, trivalent influenza vaccine was safe and well tolerated and induced high levels of seroconversion and seroprotection rates. These clinical data are a first step towards demonstrating the feasibility of producing the vaccine locally and that seasonal vaccine production in Vietnam may be an effective strategy for enhancing the global influenza vaccine supply. ClinicalTrials.gov number NCT02598089, October 15, 2015.

Immunogenicity of quadrivalent HPV vaccine among girls 11 to 13 Years of age vaccinated using alternative dosing schedules: results 29 to 32 months after third dose.

BACKGROUND: Immune response to quadrivalent human papillomavirus (HPV) vaccine delivered at 0, 2, and 6 months in young adolescent females plateaus around 24 months after immunization. Antibody levels >24 months postvaccination using extended dosing schedules is unknown. METHODS: We conducted a follow-up immunogenicity study of adolescent girls in Vietnam who participated in a noninferiority trial to investigate whether immune responses using 3 alternative dosing schedules (0, 3, 9 months; 0, 6, 12 months; or 0, 12, 24 months) are noninferior to the standard schedule at >2 years after immunization. RESULTS: Quadrivalent HPV vaccine immunogenicity delivered on 3 alternative dosing schedules was noninferior for types 6, 11, 16, and 18 at 32 months post-dose 3 compared to the standard schedule. Pre-dose 3 antibody levels for the 0, 12, 24 month schedule were similar to those measured 32-months post-dose 3. CONCLUSIONS: We found similar antibody concentrations ≥29 months after 3 doses of HPV vaccine regardless of dose-timing, and extended schedules do not produce inferior immune responses. Our findings also suggested that 2 doses of HPV vaccine delivered at 0 and 12 months might afford similar protection. Evidence supporting dosing flexibility could be important for national HPV vaccination policies.

Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial.

CONTEXT: Human papillomavirus (HPV) vaccine programs may decrease the morbidity and mortality due to cervical cancer seen among women in low-resource countries. However, the 3-dose schedule over a 6-month period is a potential barrier to vaccine introduction in such settings. OBJECTIVE: To determine the immunogenicity and reactogenicity of different dosing schedules of quadrivalent HPV vaccine in adolescent girls in Vietnam. DESIGN, SETTING, AND PARTICIPANTS: Open-label, cluster randomized, noninferiority study (conducted between October 2007 and January 2010) assessing 4 schedules of an HPV vaccine delivered in 21 schools to 903 adolescent girls (aged 11-13 years at enrollment) living in northwestern Vietnam. INTERVENTION: Intramuscular injection of 3 doses of quadrivalent HPV vaccine delivered on a standard dosing schedule (at 0, 2, and 6 months) and 3 alternative dosing schedules (at 0, 3, and 9 months; at 0, 6, and 12 months; or at 0, 12, and 24 months). MAIN OUTCOME MEASURES: Serum anti-HPV geometric mean titers (GMT) measured 1 month after the third dose of the HPV vaccine was administered; GMT was determined by type-specific competitive immunoassay. Noninferiority of each alternative vaccination dosing schedule was achieved if the lower bound of the multiplicity-adjusted confidence interval (CI) of the type-specific GMT ratio for HPV-16 and HPV-18 was greater than 0.5 (primary outcome). Safety outcomes were immediate reactions, local reactions, fever within 7 days after each dose, and serious adverse events up to 30 days following the last dose. RESULTS: In the intention-to-treat analysis, 809 girls who received at least 1 HPV vaccine dose had valid serum measurements 1 month after the third dose. After the third dose, the GMTs for those in the standard schedule group who received doses at 0, 2, and 6 months were 5808.0 (95% CI, 4961.4-6799.0) for HPV-16 and 1729.9 (95% CI, 1504.0-1989.7) for HPV-18; 5368.5 (95% CI, 4632.4-6221.5) and 1502.3 (95% CI, 1302.1-1733.2), respectively, for those whose received doses at 0, 3, and 9 months; 5716.4 (95% CI, 4876.7-6700.6) and 1581.5 (95% CI, 1363.4-1834.6), respectively, for those who received doses at 0, 6, and 12 months; and 3692.5 (95% CI, 3145.3-4334.9) and 1335.7 (95% CI, 1191.6-1497.3), respectively, for those who received doses at 0, 12, and 24 months. Noninferiority criteria were met for the alternative schedule groups that received doses at 0, 3, and 9 months (HPV-16 GMT ratio: 0.92 [95% CI, 0.71-1.20]; HPV-18 GMT ratio: 0.87 [95% CI, 0.68-1.11]) and at 0, 6, and 12 months (HPV-16 GMT ratio: 0.98 [95% CI, 0.75-1.29]; HPV-18 GMT ratio: 0.91 [95% CI, 0.71-1.17]). Prespecified noninferiority criteria were not met for the alternative schedule group that received doses at 0, 12, and 24 months (HPV-16 GMT ratio: 0.64 [95% CI, 0.48-0.84]; HPV-18 GMT ratio: 0.77 [95% CI, 0.62-0.96]). Pain at the injection site was the most common adverse event. CONCLUSIONS: Among adolescent girls in Vietnam, administration of the HPV vaccine on standard and alternative schedules was immunogenic and well tolerated. The use of 2 alternative dosing schedules (at 0, 3, and 9 months and at 0, 6, and 12 months) compared with a standard schedule (at 0, 2, and 6 months) did not result in inferior antibody concentrations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00524745.

Disability from Japanese encephalitis in Cambodia and Viet Nam.

A cohort of Japanese encephalitis (JE) survivors in Cambodia and Viet Nam were assessed at least 4 months after hospital discharge in order to understand the extent of disability after JE. We used a simple assessment tool which focuses on the impact on daily life. In total, 64 disability assessments were conducted: 38 in Cambodia and 26 in Viet Nam. In Cambodia, 4 (11%) children had severe sequelae, suggesting the children would likely be dependent, 15 (39%) had moderate sequelae and 17 (45%) had mild sequelae. In Viet Nam, two (8%) persons had severe sequelae, five (19%) had moderate sequelae and eight (31%) had mild sequelae. In many JE-endemic areas there are no multi-disciplinary teams with sophisticated equipment to assess patients after JE disease. This assessment tool can assist with patient management and generate data to support the need for programmes to prevent disease and improve outcomes for survivors.

Immunogenicity of a locally produced hepatitis B vaccine with the birth dose stored outside the cold chain in rural Vietnam.

The heat stability of hepatitis B vaccine (HepB vaccine) should enable its storage outside the cold chain (OCC), increasing access to the birth dose in areas lacking refrigeration. We compared the immunogenicity of a locally produced vaccine among infants who received three doses stored within the cold chain (n = 358) or for whom the first dose was stored OCC for up to one month (n = 748). Serum was collected from these infants at age 9-18 months. The vaccine was protective in 80.3% of all infants. There were no differences in the prevalence of a protective level of antibody or antibody titer among groups of infants according to storage strategy. Differences in antibody titer between certain groups of infants could be explained by different vaccination schedules. Where birth dose coverage will be improved, HepB vaccine can be taken OCC for up to one month without affecting its immunogenicity.