Vaccine Manufacturing Capacity Research Articles

Challenges of Developing Novel Vaccines and Large Scale Production Issues

Live attenuated and inactivated pathogens, as well as subunit vaccinations, can give long-term protection against a variety of deadly diseases. Despite this progress, vaccine development for a number of infectious diseases, particularly those that are more capable of evading the adaptive immune response, remains a serious issue. Furthermore, the fundamental impediment to the greatest uptake of virus vaccines isn’t usually the efficacy of conventional procedures, but rather the requirement for more fast research and large-scale manufacture. As a result, the development of more powerful and adaptable vaccine platforms is critical. The complexities of developing the manufacturing process, formulation, and analytical assays, as well as the problem of scientific assay optimization, are the most well-known barriers to vaccine development failures or delays. Scientists argue that the extremely concentrated state of global vaccine manufacturing capacity limits large-scale vaccine production. At the moment, only a few countries have the capacity to make vaccines on their own. Scaling up vaccine production is difficult, and a shortage of manufacturing sites is limiting global vaccine availability. Vaccine manufacturing and the development of breakthrough technologies capable of producing huge quantities of vaccines against known and undiscovered infections are difficult tasks nowadays. Vaccines can be made as suspensions, emulsions, or freeze-dried powders with a variety of adjuvants. However, many of those manufactured vaccines face multiple problems from a pharmaceutical standpoint, including the risk for acute hypersensitivity reactions, the need for extremely cold storage temperatures, and handling and delivery requirements. These requirements should limit vaccine supply to different populations, which has a negative impact on health equity. In the production of vaccines during upstream and downstream processes, new facilities, equipment, and enabling technology may be required, some of which may have an impact on how existing vaccines are manufactured. Despite these advancements, long-standing difficult circumstances will persist or worsen. Despite the fact that the number of individuals required is significantly less than in massive phase 3 studies, pharmacokinetic investigations can be logistically challenging and expensive. Even if there are challenging scenarios for implementing new pharmacokinetic models, there may be significant value in doing so, even in the context of an approved medication. The use of this ethically complex and contentious method for vaccine evaluation would necessitate interdisciplinary, global oversight to ensure that the results are rigorous and justify the potential dangers to participants and their communities.

International Efforts and Next Steps to Advance COVID-19 Vaccines Research and Production in Low- and Middle-Income Countries.

Equitable and efficient distribution of COVID-19 vaccines continues to be a key issue in global health, and a targeted approach is needed to meet the World Health Organization’s world vaccination targets. Although some low- and middle-income countries (LMICs) are developing their own vaccines to address the distribution problem, legal and technical challenges have had a negative impact on productivity. This article explores relevant international legal instruments that can enable faster research and development of COVID-19 vaccines in LMICs, focusing on the role of biosafety standards, biological materials transfer, and key knowledge sharing. Our analysis has established that the potential of existing global health legal instruments has yet to be realized in order to close the productivity gap in LMICs and strengthen their vaccine manufacturing capacity. Additionally, mutual recognition of vaccine efficacy has become a new challenge for achieving global vaccination targets. We argue that the World Health Organization should continue its leading position by developing a more practical and targeted framework to help LMICs overcome challenges arising from technology transfer, knowledge sharing, and politics.

The Political Economy of Global Vaccine Nationalism: Towards Building Agency for Africa’s Drug Manufacturing Capacity

ABSTRACT Since the World Health Organization declared Covid-19 a global pandemic in early 2020, several countries have moved from non-pharmaceutical interventions in combatting the Covid-19 pandemic to developing vaccine acquisition strategies. Many developed countries adopted strategies to secure and stockpile vaccines. Pharmaceutical firms used their bargaining power to negotiate steep vaccine prices in developing nations. Vaccine nationalism and the predatory behavior of pharmaceutical firms make the case for temporarily lifting intellectual property protections a morally compelling one. African countries must work together to build vaccine manufacturing capacity through scientific cooperation, development of human capital, and nurturing of value chains.

International Economic Law and the COVID-19 sanitary crisis: an introduction

The sanitary crisis has already had a substantial influence on the global economy, with restrictions on sanitary material exports, interruption of international transportation, increased screening of foreign investment, and challenges to intellectual property rights. It has compelled states to reconsider their core interests and national security, for example, in terms of maintaining pharmaceutical and vaccine manufacturing capacity. In addition, the lockdowns adopted in many countries have raised questions about their conformity with the existing free trade and investment treaties, and about the rationale of exceptions and derogations in these treaties. The economic consequences of the crisis have resulted in huge stimulus packages by national governments, putting a strain on the public exchequer and increasing debt. Financial experts also anticipate that the public debt to GDP ratio of most developed as well as emerging nations would further skyrocket and therefore the IMF, development banks, and other international financial institutions have been mobilized to meet the current and forthcoming financial needs of the most affected economies. Consequently, these diverse topics need a legal discussion, with an emphasis on the States' unique reactions and practices in their economic interactions, as well as the possibility of a post-COVID-19 world economic order.

Science, Innovation, and Society in the Age of Pandemics: Reflections From the Inaugural Sir Alasdair Breckenridge Lecture.

Science, Innovation, and Society in the Age of Pandemics: Reflections From the Inaugural Sir Alasdair Breckenridge Lecture.

Beyond vaccine hesitancy: time for Africa to expand vaccine manufacturing capacity amidst growing COVID-19 vaccine nationalism

In The Lancet Microbe, Paul Adepoju provides a report1 on how Africa lags behind in the global race to rollout COVID-19 mass vaccination. This race is unprecedented and characterised by high-income countries adopting strategies such as pre-ordering millions of doses before the COVID-19 vaccines completed clinical trials. Africa has now embarked on the biggest immunisation drive in history with the aim of achieving 60% population coverage with the COVID-19 vaccine by June, 2022, through the WHO-led COVAX facility.

A Nonprofit Public Utility Approach to Enhance Next-Generation Vaccine Manufacturing Capacity.

A Nonprofit Public Utility Approach to Enhance Next-Generation Vaccine Manufacturing Capacity.

Building the global vaccine manufacturing capacity needed to respond to pandemics

Building the global vaccine manufacturing capacity needed to respond to pandemics

Viral Sovereignty, Vaccine Diplomacy, and Vaccine Nationalism: The Institutions of Global Vaccine Access

Viral Sovereignty, Vaccine Diplomacy, and Vaccine Nationalism: The Institutions of Global Vaccine Access

COVID-19 Crisis in India: Threats and Opportunities

Covid-19 catastrophe in India during the first half of 2021 has been a matter of great concern for policy makers, health institutions and the government. A country of 1.4 billion has passed 29m Covid-19 infections and 351,300 deaths. India is likely to have more new cases per day from the beginning of August 2021. Strains of Concern and the Strains of Interest (new and emerging mutants have contributed to increased morbidity and mortality. Emergence of mucormycosis (black fungus) during the ongoing pandemic is a bigger challenge to India, Action on a war-footing is needed to save lives by expanding and upgrading healthcare facilities more so in rural areas. 233 million doses of the COVID vaccine have been given in India. More than 45 million people have received two doses of the vaccine (fully vaccinated). The third Phase of the vaccination has coincided with an acute vaccine supply shortage across the country. India’s monthly COVID vaccine manufacturing capacity is about 60-65 million doses against the final requirement of 1.45 billion doses to cover 70 per cent adults. Investing in health is crucial. India’s health system is overwhelmed. Hospitals are running out of oxygen supplies, ventilators and beds. It is a situation that needs a global approach. Tiding over a pandemic requires detailed preparation at multiple levels on the part of the State. Vaccination drive to cover all is crucial. Global partners have a responsibility to support India in mass production of vaccines. Developed economies must support the scale-up of lab testing and genomic sequencing of virus. Developed nations should also provide technical assistance, help India in training its health professionals and provide logistic support (oxygen canisters/concentrators/cylinders/ medications/PPEs, establishing/operationalising field hospitals/quarantine centres), strengthening surveillance systems, data management like accurate reporting of cases and deaths besides temporality taking out manufacturing of life-saving vaccines/drugs from India to other parts of the world during the crisis.

India’s COVID-19 Catastrophe: Cause, Effect & Future Trends

The COVID crisis in India shows no sign of abating. The country of 1.4 billion has passed 30.5 million COVID-19 infections and over 402,000 deaths. Even government figures are likely underestimated due to problems with testing and reporting in the country. Reasonable estimates due to under reporting and lack of testing put these figures at three times higher. The new cases and deaths are predicted to rise by September 2021. The situation is bad in the main cities, but also that it is worse in the poorer and rural areas where lack of healthcare resources has made those populations most vulnerable to the disease. There is an urgent need for rapid tests for quantification of infectiousness to triage patients. In traumatised India, saving lives has become the highest priority to be achieved by vaccinating 70 per cent of the adult population. Over 200 million population have been vaccinated. India’s monthly COVID vaccine manufacturing capacity is about 60 - 65 million doses against the final requirement of 1.45 billion doses to cover 70 per cent adults. Even though the second surge is on a decline in most of the states, mucormycosis continues to be a public health concern. There are 41,000 mucormycosis cases reported during the second wave. Daily increase in Delta plus variant cases should alert the Policy-makers. It has a very high transmissibility. Genomic testing & surveillance of mutations to limit fresh twist of pandemic is a necessity. Only a few drugs have emerged as approved COVID-19 treatments. Where are we with drug treatment? Over 30 billion USD have been spent on vaccine development because it has a market. Very little is spent on research on drug discovery. There has not been any significant antibiotic molecule for the last two decades. Politics has played and continues to play a big part in the spread of the virus but it is a situation that needs a global approach. Tiding over a pandemic requires detailed preparation at multiple levels on the part of the State. New ways to prevent, detect, track and treat SARS-CoV-2 infections are crucial keeping in view the rise of more-transmissible viral mutants like Delta plus.

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.

Introduction of pentavalent vaccine in Indonesia: a policy analysis.

The introduction of pentavalent vaccine containing Haemophilus influenzae type b antigen in Indonesia’s National Immunization Program occurred nearly three decades after the vaccine was first available in the United States and 16 years after Indonesia added hepatitis B vaccine into the program. In this study, we analyzed the process that led to the decision to introduce pentavalent vaccine in Indonesia. Using process tracing and case comparison, we used qualitative data gathered through interviews with key informants and data extracted from written sources to identify four distinct but interrelated processes that were involved in the decision making: (a) pentavalent vaccine use policy process, (b) financing process, (c) domestic vaccine development process and (d) political process. We hypothesized that each process is associated with four necessary conditions that are jointly sufficient for the successful introduction of pentavalent vaccine in Indonesia, namely (a) an evidence-based vaccine use recommendation, (b) sufficient domestic financing capacity, (c) sufficient domestic vaccine manufacturing capacity and (d) political support for introduction. This analysis of four processes that led to the decision to introduce a new vaccine in Indonesia may help policy makers and other stakeholders understand and manage activities that can accelerate vaccine introduction in the future.

GLA-AF, an Emulsion-Free Vaccine Adjuvant for Pandemic Influenza

The ongoing threat from Influenza necessitates the development of new vaccine and adjuvant technologies that can maximize vaccine immunogenicity, shorten production cycles, and increase global vaccine supply. Currently, the most successful adjuvants for Influenza vaccines are squalene-based oil-in-water emulsions. These adjuvants enhance seroprotective antibody titers to homologous and heterologous strains of virus, and augment a significant dose sparing activity that could improve vaccine manufacturing capacity. As an alternative to an emulsion, we tested a simple lipid-based aqueous formulation containing a synthetic TLR4 ligand (GLA-AF) for its ability to enhance protection against H5N1 infection. GLA-AF was very effective in adjuvanting recombinant H5 hemagglutinin antigen (rH5) in mice and was as potent as the stable emulsion, SE. Both adjuvants induced similar antibody titers using a sub-microgram dose of rH5, and both conferred complete protection against a highly pathogenic H5N1 challenge. However, GLA-AF was the superior adjuvant in ferrets. GLA-AF stimulated a broader antibody response than SE after both the prime and boost immunization with rH5, and ferrets were better protected against homologous and heterologous strains of H5N1 virus. Thus, GLA-AF is a potent emulsion-free adjuvant that warrants consideration for pandemic influenza vaccine development.

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.