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In 2009, a novel A(H1N1) influenza virus emerged with rapid human-to-human spread and caused the first pandemic of the 21st century. Although this pandemic was considered mild compared to the previous pandemics of the 20th century, there was still extensive disease and death. This virus replaced the previous A(H1N1) and continues to circulate today as a seasonal virus. It is well established that vaccines are the most effective method to alleviate the mortality and morbidity associated with influenza virus infections, but the 2009 A(H1N1) influenza pandemic, like all significant infectious disease outbreaks, presented its own unique set of problems with vaccine supply and demand. This manuscript describes the issues that confronted governments, international agencies and industries in developing a well-matched vaccine in 2009, and identifies the key improvements and remaining challenges facing the world as the next influenza pandemic inevitably approaches.

► Non-adjuvanted, whole virus A/Indonesia/05/2005 H5N1 Vero cell-derived influenza vaccine induced high seroprotection rates. ► 11/12 CHMP criteria were fulfilled. ► Cross-reactive response against heterologous A/Vietnam/1203/2004 strain. ► Well tolerated vaccine, no SAEs reported. A successful vaccine development strategy for areas with clustered H5N1 events requires conduct of vaccine trials in potentially non-naïve subjects and evaluation of post-vaccination responsiveness. An open-label, randomized, phase I/II study therefore assessed the immunogenicity and safety of two different dose levels of an inactivated, non-adjuvanted, whole virus clade 2.1 (A/Indonesia/05/2005) H5N1 Vero cell-derived influenza vaccine in healthy adults (21–45 years) from a region where the virus has been circulating (Hong Kong) as well as Singapore. Subjects ( N = 110) were randomized 1:1 to receive two vaccinations with either 3.75 μg or 7.5 μg H5N1 haemagglutinin antigen 21 days apart. Safety, immunogenicity (microneutralization [MN] and single radial haemolysis [SRH] at baseline and post-vaccination) and cross-reactivity against a heterologous clade 1 strain (A/Vietnam/1203/2004) of the vaccine were assessed. Pre-existing immunity to the vaccine strain was 14% which is higher than previously reported for these regions. Two vaccinations with either vaccine formulation induced high seroprotection rates (MN titre ≥ 1:20) against the vaccine strain A/Indonesia/05/2005: 82.7% and 86.5% in the 3.75 μg and 7.5 μg dose groups. Seroconversion rates and fold increase exceeded the CPMP criterion of >40% and >2.5 for MN and SRH in both dose groups after the second vaccination, while the seroprotection rate in the 7.5 μg dose group determined by SRH was only marginally lower (69.2%) than the CPMP criterion of >70%. Thus, 11 of 12 CHMP criteria were fulfilled. A cross-reactive antibody response against the heterologous A/Vietnam/1203/2004 strain was demonstrated after the second vaccination (>21% by MN and ≥25% by SRH). Persistence of antibodies against the vaccine strain was also demonstrated 6 months after the first vaccination, indicating that a booster vaccination would be effective in those who have received two priming doses. No serious adverse events were reported. The H5N1 influenza vaccine against clade 2.1 strain A/Indonesia/05/2005 was well tolerated and immunogenic after two vaccinations, and induced a cross-neutralizing antibody response, with no dose effect.

A quantitative method is presented to rank strengths, weaknesses, opportunities, and threats (SWOT) of modified vaccinia virus Ankara (MVA) as a platform for pre-pandemic and pandemic influenza vaccines. Analytic hierarchy process (AHP) was applied to achieve pairwise comparisons among SWOT factors in order to prioritize them. Key opinion leaders (KOLs) in the influenza vaccine field were interviewed to collect a unique dataset to evaluate the market potential of this platform. The purpose of this study, to evaluate commercial potential of the MVA platform for the development of novel generation pandemic influenza vaccines, is accomplished by using a SWOT and AHP combined analytic method. Application of the SWOT–AHP model indicates that its strengths are considered more important by KOLs than its weaknesses, opportunities, and threats. Particularly, the inherent immunogenicity capability of MVA without the requirement of an adjuvant is the most important factor to increase commercial attractiveness of this platform. Concerns regarding vector vaccines and anti-vector immunity are considered its most important weakness, which might lower public health value of this platform. Furthermore, evaluation of the results of this study emphasizes equally important role that threats and opportunities of this platform play. This study further highlights unmet needs in the influenza vaccine market, which could be addressed by the implementation of the MVA platform. Broad use of MVA in clinical trials shows great promise for this vector as vaccine platform for pre-pandemic and pandemic influenza and threats by other respiratory viruses. Moreover, from the results of the clinical trials seem that MVA is particularly attractive for development of vaccines against pathogens for which no, or only insufficiently effective vaccines, are available.

Vaccination plays an important role in pandemic planning and response. The possibility of developing an effective vaccine for a novel pandemic virus is not assured. However, as we have seen with SARS-CoV-2 vaccine development, with sufficient resources and global focus, successful outcomes can be achieved in a relatively short period. However even when vaccine is available it will initially be scarce. When one becomes available, how should it be distributed? In this paper we explicate how ethical thinking that is carefully attuned to context is essential to decisions about how we should conduct vaccination in a pandemic where demand exceeds supply. We focus on two key issues. First, setting the aims for a pandemic vaccination programme. Second, thinking about the means of delivering a chosen aim. We outline how pandemic vaccine distribution strategies can be implemented with distinct aims, e.g. protecting groups at greater risk of harm, saving the most lives, or ensuring societal benefit. Each aim will result in a focus on a different priority population and each strategy will have a different benefit-harm profile. Once we have decided our aim, we still have choices to make about delivery. We may achieve at least some ends via direct or indirect strategies. Such policy decisions are not merely technical, but necessarily involve ethics. One important general issue is that such planning decisions about distribution will always be made under conditions of uncertainty about vaccine safety and effectiveness. However, planning how to distribute vaccine for SARS-CoV-2 is even harder because we understand relatively little about the virus, transmission, and its immunological impact in the short and long term.

Allocation of scarce resources during a pandemic extends to the allocation of vaccines when they eventually become available. We describe a framework for priority vaccine allocation that employed a cross-disciplinary approach, guided by ethical considerations and informed by local risk assessment. Published and grey literature was reviewed, and augmented by consultation with key informants, to collate past experience, existing guidelines and emerging strategies for pandemic vaccine deployment. Identified ethical issues and decision-making processes were also included. Concurrently, simulation modelling studies estimated the likely impacts of alternative vaccine allocation approaches. Assembled evidence was presented to a workshop of national experts in pandemic preparedness, vaccine strategy, implementation and ethics. All of this evidence was then used to generate a proposed ethical framework for vaccine priorities best suited to the Australian context. Published and emerging guidance for priority pandemic vaccine distribution differed widely with respect to strategic objectives, specification of target groups, and explicit discussion of ethical considerations and decision-making processes. Flexibility in response was universally emphasised, informed by real-time assessment of the pandemic impact level, and identification of disproportionately affected groups. Model outputs aided identification of vaccine approaches most likely to achieve overarching goals in pandemics of varying transmissibility and severity. Pandemic response aims deemed most relevant for an Australian framework were: creating and maintaining trust, promoting equity, and reducing harmful outcomes. Defining clear and ethically-defendable objectives for pandemic response in context aids development of flexible and adaptive decision support frameworks and facilitates clear communication and engagement activities.

•Children’s uptake of the 2009 pandemic influenza vaccine was studied in a birth cohort.•Children of young or lowly educated mothers were at risk of not receiving the vaccine.•Psychosocial well-being of parents was not associated with children’s vaccinations.•These lessons from the 2009 influenza can be utilized during the current COVID-19 pandemic. Before COVID-19, the previous pandemic was caused by influenza A(H1N1)pdm09 virus in 2009. Identification of factors behind parental decisions to have their child vaccinated against pandemic influenza could be helpful in planning of other pandemic vaccination programmes. We investigated the association of parental socioeconomic and psychosocial factors with uptake of the pandemic influenza vaccine in children in 2009–2010. This study was conducted within a prospective birth-cohort study (STEPS Study), where children born in 2008–2010 are followed from pregnancy to adulthood. Demographic and socioeconomic factors of parents were collected through questionnaires and vaccination data from electronic registers. Before and after the birth of the child, the mother’s and father’s individual and relational psychosocial well-being, i.e. depressive symptoms, dissatisfaction with the relationship, experienced social and emotional loneliness, and maternal anxiety during pregnancy, were measured by validated questionnaires (BDI-II, RDAS, PRAQ, and UCLA). Of 1020 children aged 6–20 months at the beginning of pandemic influenza vaccinations, 820 (80%) received and 200 (20%) did not receive the vaccine against influenza A(H1N1)pdm09. All measures of parents’ psychosocial well-being were similar between vaccinated and non-vaccinated children. Children of younger mothers had a higher risk of not receiving the influenza A(H1N1)pdm09 vaccine than children of older mothers (OR 2.59, 95% CI 1.52–4.43, for mothers < 27.7 years compared to ≥ 33.6 years of age). Children of mothers with lower educational level had an increased risk of not receiving the vaccine (OR 1.46, 95% CI 1.00–2.14). Mother’s younger age and lower education level were associated with an increased risk for the child not to receive the 2009 pandemic influenza vaccine, but individual or relational psychosocial well-being of parents was not associated with children’s vaccination. Our findings suggest that young and poorly educated mothers should receive targeted support in order to promote children’s vaccinations during a pandemic.

•MF59-adjuvanted, cell-based flu vaccine (aH5N1c) may be advantageous in a pandemic.•aH5N1c elicited robust antibody responses to heterologous A/H5N1 strains.•Responses were higher when assayed with microneutralization than HI. Vaccines are the main prophylactic measure against pandemic influenza. Adjuvanted, cell culture–derived vaccines, which are not subject to limitations of egg-based vaccine production, have the potential to elicit an antibody response against heterologous strains and may be beneficial in the event of an A/H5N1 pandemic. A prespecified exploratory analysis of data from a phase 2, randomized, controlled, observer-blind multicenter trial (NCT01776554) to evaluate the immunogenicity of a MF59-adjuvanted, cell culture–based A/H5N1 influenza vaccine (aH5N1c), containing 7.5 µg hemagglutinin antigen per dose, in subjects 6 months through 17 years of age was conducted. Geometric mean titers (GMT) were determined using hemagglutination inhibition (HI) and microneutralization (MN) assays, and proportions of patients achieving seroconversion, HI and MN titers ≥ 1:40, and a 4-fold increase in MN titers against 5 heterologous strains (influenza A/H5N1 Anhui/2005, Egypt/2010, Hubei/2010, Indonesia/2005, and Vietnam/1203/2004) three weeks after administration of the second dose were assessed. After the second dose, HI GMTs against heterologous strains increased between 8- and 40-fold, and MN GMTs increased 13- to 160-fold on Day 43 vs Day 1. On Day 43, 32–72% of subjects had HI titers ≥ 1:40 and achieved seroconversion against the heterologous strains. Using the MN assay, 84–100% of subjects had MN titers ≥ 1:40 and 83–100% achieved an at least 4-fold increase in MN titers against the heterologous strains. The highest responses were consistently against A/H5N1 Egypt/2010. When given to children aged 6 months through 17 years, aH5N1c resulted in increased immunogenicity from baseline against all 5 heterologous A/H5N1 strains tested, demonstrating the potential of an MF59-adjuvanted, cell-derived A/H5N1 vaccine to provide cross-protection against other A/H5N1 strains (NCT01776554).

•A HI titer of 40 was considered to be equivalent to a MN titer of 80.•AS03-adjuvanted H5N1 vaccine induced good homologous neutralizing antibody responses.•Non-adjuvanted vaccine induced a weak homologous antibody response in naïve subjects.•Non-adjuvanted booster vaccination induced strong and long-lasting heterologous responses. Avian influenza A(H5N1) viruses have caused sporadic infections in humans and thus they pose a significant global health threat. Among symptomatic patients the case fatality rate has been ca. 50%. H5N1 viruses exist in multiple clades and subclades and several candidate vaccines have been developed to prevent A(H5N1) infection as a principal measure for preventing the disease. Serum antibodies against various influenza A(H5N1) clade viruses were measured in adults by ELISA-based microneutralization and haemagglutination inhibition tests before and after vaccination with two different A(H5N1) vaccines in 2009 and 2011. Two doses of AS03-adjuvanted A/Indonesia/5/2005 vaccine induced good homologous but poor heterologous neutralizing antibody responses against different clade viruses. However, non-adjuvanted A/Vietnam/1203/2004 booster vaccination in 2011 induced very strong and long-lasting homologous and heterologous antibody responses while homologous response remained weak in naïve subjects. Sequential vaccination with two different A(H5N1) pre-pandemic vaccines induced long-lasting high level cross-clade immunity against influenza A(H5N1) strains, thus supporting a prime-boost vaccination strategy in pandemic preparedness plans.

Influenza viruses are responsible for millions of cases globally and significantly threaten public health. Since pandemic and zoonotic influenza viruses have emerged in the last 20 years and some of the viruses have resulted in high mortality in humans, a universal influenza vaccine is needed to provide comprehensive protection against a wide range of influenza viruses. Current seasonal influenza vaccines provide strain-specific protection and are less effective against mismatched strains. The rapid antigenic drift and shift in influenza viruses resulted in time-consuming surveillance and uncertainty in the vaccine protection efficacy. Most recent universal influenza vaccine studies target the conserved antigen domains of the viral surface glycoproteins and internal proteins to provide broader protection. Following the development of advanced vaccine technologies, several innovative strategies and vaccine platforms are being explored to generate robust cross-protective immunity. This review provides the latest progress in the development of universal influenza vaccines.

Coronaviruses are named after the crown-like spike proteins on their surface. In the 21st century, three coronaviruses, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome related coronavirus (MERS-CoV), have emerged in the human population, presumably evolving from pathogens infecting other animals. Coronaviruses are enveloped viruses responsible for 15-30% of the atypical pneumonia cases in humans worldwide. The current coronavirus disease 2019 (COVID-19) pandemic is caused by the newest SARS virus, SARS-CoV-2, an enveloped, positive-sense, single-stranded RNA betacoronavirus of the family Coronaviridae. As of April 2021, the World Health Organization has reported more than 3 million deaths from COVID-19 and more than 140 million people have been infected with the virus, thereby making it the worst SARS pandemic of all time. Here, I review the current understanding of the molecular biology of coronaviruses and their host interactions, bringing together knowledge of the infection process to aid in the development of therapeutic drugs and/or vaccines against SARS-CoV-2. I also briefly overview the current situation of available treatments, vaccinations, and emerging strains.