Influenza Vaccine Manufacturing Capacity Research Articles

Preparedness against pandemic influenza: Production of an oil-in-water emulsion adjuvant in Brazil.

Increasing pandemic influenza vaccine manufacturing capacity is considered strategic by WHO. Adjuvant use is key in this strategy in order to spare the vaccine doses and by increasing immune protection. We describe here the production and stability studies of a squalene based oil-in-water emulsion, adjuvant IB160, and the immune response of the H7N9 vaccine combined with IB160. To qualify the production of IB160 we produced 10 consistency lots of IB160 and the average results were: pH 6.4±0.05; squalene 48.8±.0.03 mg/ml; osmolality 47.6±6.9 mmol/kg; Z-average 157±2 nm, with polydispersity index (PDI) of 0.085±0.024 and endotoxin levels <0.5 EU/mL. The emulsion particle size was stable for at least six months at 25°C and 24 months at 4–8°C. Two doses of H7N9 vaccine formulated at 7.5 μg/dose or 15 μg/dose with adjuvant IB160 showed a significant increase of hemagglutination inhibition (HAI) titers in sera of immunized BALB/c mice when compared to control sera from animals immunized with the H7N9 antigens without adjuvant. Thus the antigen-sparing capacity of IB160 can potentially increase the production of the H7N9 pandemic vaccine and represents an important achievement for preparedness against pandemic influenza and a successful North (IDRI) to South (Butantan Institute) technology transfer for the production of the adjuvant emulsion IB160.

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)

BackgroundA 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. MethodsThis 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. ResultsThe 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. ConclusionThe 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.

Quadrivalent influenza vaccines in low and middle income countries: Cost-effectiveness, affordability and availability

In high-income countries, there is an increased tendency to replace inactivated seasonal trivalent influenza (TIV) vaccines with quadrivalent (QIV) vaccines as these are considered to give a greater public health benefit. In addition, several recent studies from the USA and Europe indicate that replacement with QIV might also be cost-effective; however, the situation in low- and middle-income countries (LMIC) is less clear as few studies have investigated this aspect.The paper by de Boer et al. (2018) describes a dynamic modelling study commissioned by WHO that suggests that in LMICs, under certain conditions, QIV might also be more cost-effective than TIV. In this commentary, we discuss some important aspects that policymakers in LMICs might wish to take into account when considering replacing TIV by QIV.Indeed, from the data presented in the paper by de Boer et al. it can be inferred that replacing QIV for TIV would mean a 25–29% budget increase for seasonal influenza vaccination in South Africa and Vietnam, resulting in an incremental influenza-related health impact reduction of only 7–8% when a 10% symptomatic attack rate is assumed. We argue that national health budget considerations in LMIC might lead decision-makers to choose other investments with higher health impact for a budget equivalent to roughly a quarter of the yearly TIV immunization costs.In addition to an increased annual cost that would be associated with a decision to replace TIV with QIV, there would be an increased pressure on manufacturers to produce QIV in time for the influenza season requiring manufacturers to produce some components of the seasonal vaccine at risk prior to the WHO recommendations for influenza vaccines.Unless the current uncertainties, impracticalities and increased costs associated with QIVs are resolved, TIVs are likely to remain the more attractive option for many LMICs. Each country should establish its context-specific process for decision-making based on national data on disease burden and costs in order to determine whether the health gains out-weigh the additional cost of moving to QIV. For example, immunizing more people in the population, especially those in higher risk groups, with TIV might not only provide better value for money but also deliver better health outcomes in LMICs.Countries with local influenza vaccine manufacturing capacity should include in their seasonal influenza vaccine procurement process an analysis of the pros- and cons- of TIV versus QIV, to ensure both feasibility and sustainability of local manufacturing.

Advancing new vaccines against pandemic influenza in low-resource countries.

With the support of the Biomedical Advanced Research and Development Authority (BARDA), PATH is working with governments and vaccine manufacturers to strengthen their influenza vaccine manufacturing capacity and improve their ability to respond to emerging pandemic influenza viruses. Vaccines directed against influenza A/H5N1 and A/H7N9 strains are a particular focus, given the potential for these viruses to acquire properties that may lead to a pandemic. This paper will review influenza vaccine development from a developing country perspective and PATH's support of this effort. Several vaccines are currently in preclinical and clinical development at our partners for seasonal and pandemic influenza in Vietnam (IVAC and VABIOTECH), Serbia (Torlak), China (BCHT), Brazil (Butantan), and India (SII). Products in development include split, whole-virus inactivated and live attenuated influenza vaccines (LAIVs). Additionally, while most manufacturers propagate the virus in eggs, PATH is supporting the development of cell-based processes that could substantially increase global manufacturing capacity and flexibility. We review recent data from clinical trials of pandemic influenza vaccines manufactured in developing countries. An important discussion is on the role of whole virion vaccines for H5N1, given the poor immunogenicity of split vaccines and the complexity involved in developing potent adjuvants.

Challenges and successes for the grantees and the Technical Advisory Group of WHO’s influenza vaccine technology transfer initiative

One of the aims of the WHO Global Action Plan for Influenza Vaccines (GAP) was to transfer influenza vaccine production technology to interested manufacturers and governments in developing countries, to enable greater influenza vaccine manufacturing capacity against any pandemic threat or pandemic. For this objective, the GAP was supported by an independent Technical Advisory Group (TAG) to assist WHO to select vaccine manufacturing proposals for funding and to provide programmatic support for successful grantees. While there were many challenges, for both the TAG and grantees, there were also notable successes with an additional capacity of 338–600 million pandemic vaccine doses being made possible by the programme between 2007 and 2015, and a potential capacity of more than 600 million by 2016/17 with up to one billion doses expected by 2018/19. Seasonal vaccine production was also developed in 4 countries with another 4–5 countries expected to be producing seasonal vaccine by 2018/19. The relatively small WHO investments – in time and funding – made in these companies to develop their own influenza vaccine production facilities have had quite dramatic results.

Chemistry, manufacturing and control (CMC) and clinical trial technical support for influenza vaccine manufacturers

With the support of the Biomedical Advanced Research and Development Authority (BARDA) of the US Department of Health and Human Services, PATH has contributed to the World Health Organization’s (WHO’s) Global Action Plan for Influenza Vaccines (GAP) by providing technical and clinical assistance to several developing country vaccine manufacturers (DCVMs). GAP builds regionally based independent and sustainable influenza vaccine production capacity to mitigate the overall global shortage of influenza vaccines. The program also ensures adequate influenza vaccine manufacturing capacity in the event of an influenza pandemic.Since 2009, PATH has worked closely with two DCVMs in Vietnam: the Institute of Vaccines and Medical Biologicals (IVAC) and VABIOTECH. Beginning in 2013, PATH also began working with Torlak Institute in Serbia; Instituto Butantan in Brazil; Serum Institute of India Private Ltd. in India; and Changchun BCHT Biotechnology Co. (BCHT) in China.The DCVMs supported under the GAP program all had existing influenza vaccine manufacturing capability and required technical support from PATH to improve vaccine yield, process efficiency, and product formulation. PATH has provided customized technical support for the manufacturing process to each DCVM based on their respective requirements.Additionally, PATH, working with BARDA and WHO, supported several DCVMs in the clinical development of influenza vaccine candidates progressing toward national licensure or WHO prequalification. As a result of the activities outlined in this review, several companies were able to make excellent progress in developing state-of-the-art manufacturing processes and completing early phase clinical trials. Licensure trials are currently ongoing or planned for several DCVMs.

Extended antigen sparing potential of AS03-adjuvanted pandemic H1N1 vaccines in children, and immunological equivalence of two formulations of AS03-adjuvanted H1N1 vaccines: results from two randomised trials

BackgroundPandemic influenza vaccine manufacturing capacity and distribution agility is enhanced through the availability of equivalent antigen-sparing vaccines. We evaluated equivalence in terms of immunogenicity between GlaxoSmithKline Vaccines’ A/California/7/2009 (H1N1)v-like-AS03 vaccines manufactured in Dresden (D-Pan), and Quebec (Q-Pan).MethodsIn two studies, 334 adults 18-60 years of age received 2 doses of D-Pan or Q-Pan containing 3.75 μg haemagglutinin antigen (HA) adjuvanted with AS03A administered 21 days apart, and 209 children 3-9 years of age received 1 reduced dose of D-Panor Q-Pan (0.9 μg HA) or Q-Pan (1.9 μg HA) with AS03B. Haemagglutination inhibition (HI) titres were assessed before and 21 days post-vaccination. HI persistence was assessed after 12 months in adults and 6 months in children.ResultsPre-defined criteria for immunological equivalence of Q-Pan versus D-Pan were achieved in both populations. After one vaccine dose, ≥97.6% of adults and children had HI titres ≥1:40, with increases in titre ≥25.7-fold. CHMP and CBER regulatory acceptance criteria for influenza vaccines were exceeded by all groups in both studies at Day 21. In adults,the percentage with HI titres ≥1:40 at Month 12 was 82.9% (Q-Pan) and 84.0% (D-Pan). In children, the percentages at Month 6 were 75.3.3% (Q-Pan0.9), 85.1% (D-Pan0.9) and 79.3% (Q-Pan1.9). Safety profile of the study vaccines was consistent with previously published data.ConclusionTwo studies indicate that A/California/7/2009 (H1N1)v-like HA manufactured at two sites and combined with AS03 are equivalent in terms of immunogenicity in adults and children and highly immunogenic. Different HA doses elicited an adequate immune response through 180 days post-vaccination in children 3-9 years of age.Trial registrationClinicalTrials.gov: NCT00979407 and NCT01161160.

National surveillance for influenza and influenza-like illness in Vietnam, 2006−2010

Influenza virus infections result in considerable morbidity and mortality both in the temperate and tropical world. Influenza surveillance over multiple years is important to determine the impact and epidemiology of influenza and to develop a national vaccine policy, especially in countries developing influenza vaccine manufacturing capacity, such as Vietnam. We conducted surveillance of influenza and influenza-like illness in Vietnam through the National Influenza Surveillance System during 2006–2010. At 15 sentinel sites, the first two patients presenting each weekday with influenza-like illness (ILI), defined as fever and cough and/or sore throat with illness onset within 3 days, were enrolled and throat specimens were collected and tested for influenza virus type and influenza A subtype by RT-PCR. De-identified demographic and provider reported subsequent hospitalization information was collected on each patient. Each site also collected information on the total number of patients with influenza-like illness evaluated per week. Of 29,804 enrolled patients presenting with influenza-like illness, 6516 (22%) were influenza positive. Of enrolled patients, 2737 (9.3%) were reported as subsequently hospitalized; of the 2737, 527 (19%) were influenza positive. Across all age groups with ILI, school-aged children had the highest percent of influenza infection (29%) and the highest percent of subsequent hospitalizations associated with influenza infection (28%). Influenza viruses co-circulated throughout most years in Vietnam during 2006–2010 and often reached peak levels multiple times during a year, when >20% of tests were influenza positive. Influenza is an important cause of all influenza-like illness and provider reported subsequent hospitalization among outpatients in Vietnam, especially among school-aged children. These findings may have important implications for influenza vaccine policy in Vietnam.

Technology transfer of oil-in-water emulsion adjuvant manufacturing for pandemic influenza vaccine production in Romania

Many developing countries lack or have inadequate pandemic influenza vaccine manufacturing capacity. In the 2009 H1N1 pandemic, this led to delayed and inadequate vaccine coverage in the developing world. Thus, bolstering developing country influenza vaccine manufacturing capacity is urgently needed. The Cantacuzino Institute in Bucharest, Romania has been producing seasonal influenza vaccine since the 1970s, and has the capacity to produce ∼5 million doses of monovalent vaccine in the event of an influenza pandemic. Inclusion of an adjuvant in the vaccine could enable antigen dose sparing, expanding vaccine coverage and potentially allowing universal vaccination of the Romanian population and possibly neighboring countries. However, adjuvant formulation and manufacturing know-how are difficult to access. This manuscript describes the successful transfer of oil-in-water emulsion adjuvant manufacturing and quality control technologies from the Infectious Disease Research Institute in Seattle, USA to the Cantacuzino Institute. By describing the challenges and accomplishments of the project, it is hoped that the knowledge and experience gained will benefit other institutes involved in similar technology transfer projects designed to facilitate increased vaccine manufacturing capacity in developing countries.

A pandemic influenza vaccine in India: From strain to sale within 12 months

In the event of a highly pathogenic influenza pandemic, the Indian subcontinent would need 1.2 billion doses of vaccine to immunize its entire population, double if two doses were required to assure immunity. Serum Institute of India Limited (SII) thus became one of six initial grantees of the World Health Organization (WHO) technology transfer initiative to create capacity in developing countries to manufacture H5N1 pandemic influenza vaccine. At the outbreak of the A(H1N1) 2009 influenza pandemic, experience gained from the H5N1 project was used to develop a live attenuated influenza vaccine (LAIV), since this was the only option for the level of surge capacity required for a large-scale immunization campaign in India. SII took <12 months to develop and market its LAIV intranasal vaccine from receipt of the seed strain from WHO. As of November 2010, over 2.5million persons have been vaccinated with Nasovac® with no serious adverse reactions or vaccine failure after 3 months’ post-marketing surveillance. The product has been submitted for prequalification by WHO for purchase by United Nations agencies. In parallel, SII also developed an inactivated influenza vaccine, and is currently looking to ensure the sustainability of its influenza vaccine manufacturing capacity.

Influenza virus‐like particles produced by transient expression in Nicotiana benthamiana induce a protective immune response against a lethal viral challenge in mice

A strain-specific vaccine represents the best possible response to the threat of an influenza pandemic. Rapid delivery of such a vaccine to the world's population before the peak of the first infection wave seems to be an unattainable goal with the current influenza vaccine manufacturing capacity. Plant-based transient expression is one of the few production systems that can meet the anticipated surge requirement. To assess the capability of plant agroinfiltration to produce an influenza vaccine, we expressed haemagglutinin (HA) from strains A/Indonesia/5/05 (H5N1) and A/New Caledonia/20/99 (H1N1) by agroinfiltration of Nicotiana benthamiana plants. Size distribution analysis of protein content in infiltrated leaves revealed that HA was predominantly assembled into high-molecular-weight structures. H5-containing structures were purified and examination by transmission electron microscopy confirmed virus-like particle (VLP) assembly. High-performance thin layer chromatography analysis of VLP lipid composition highlighted polar and neutral lipid contents comparable with those of purified plasma membranes from tobacco plants. Electron microscopy of VLP-producing cells in N. benthamiana leaves confirmed that VLPs accumulated in apoplastic indentations of the plasma membrane. Finally, immunization of mice with two doses of as little as 0.1 microg of purified influenza H5-VLPs triggered a strong immune response against the homologous virus, whereas two doses of 0.5 microg of H5-VLPs conferred complete protection against a lethal challenge with the heterologous A/Vietnam/1194/04 (H5N1) strain. These results show, for the first time, that plants are capable of producing enveloped influenza VLPs budding from the plasma membrane; such VLPs represent very promising candidates for vaccination against influenza pandemic strains.