The 2015 global production capacity of seasonal and pandemic influenza vaccine

AbstractA global shortage and inequitable access to influenza vaccines has been cause for concern for developing countries who face dire consequences in the event of a pandemic. The Global Action Plan for Influenza Vaccines (GAP) was launched in 2006 to increase global capacity for influenza vaccine production to address these concerns. It is widely recognized that well-developed infrastructure to produce seasonal influenza vaccines leads to increased capacity to produce pandemic influenza vaccines. This article summarizes the results of a survey administered to 44 manufacturers to assess their production capacity for seasonal influenza and pandemic influenza vaccine production. When the GAP was launched in 2006, global production capacity for seasonal and pandemic vaccines was estimated to be 500million and 1.5billion doses respectively. Since 2006 there has been a significant increase in capacity, with the 2013 survey estimating global capacity at 1.5billion seasonal and 6.2billion pandemic doses. Results of the current survey showed that global seasonal influenza vaccine production capacity has decreased since 2013 from 1.504billion doses to 1.467billion doses. However, notwithstanding the overall global decrease in seasonal vaccine capacity there were notable positive changes in the distribution of production capacity with increases noted in South East Asia (SEAR) and the Western Pacific (WPR) regions, albeit on a small scale. Despite a decrease in seasonal capacity, there has been a global increase of pandemic influenza vaccine production capacity from 6.2 billion doses in 2013 to 6.4 billion doses in 2015. This growth can be attributed to a shift towards more quadrivalent vaccine production and also to increased use of adjuvants. Pandemic influenza vaccine production capacity is at its highest recorded levels however challenges remain in maintaining this capacity and in ensuring access in the event of a pandemic to underserved regions

Safety and immunogenicity of a seasonal trivalent inactivated split influenza vaccine: a phase I randomized clinical trial in healthy Serbian adults

This study was a phase I double-blind, randomized, placebo-controlled trial to evaluate the safety and immunogenicity of a Serbian-produced seasonal trivalent split, inactivated influenza vaccine in healthy adults. The vaccine was manufactured in eggs by the Torlak Institute of Virology, Vaccines and Sera, Belgrade, Serbia and contained A/H1N1, A/H3N2 and B viruses. The clinical trial took place at the Clinical Center of Serbia in Belgrade. Sixty healthy volunteers, aged 18-45years, were enrolled in the trial. On the day of immunization, volunteers were randomly assigned to receive either a single dose of the trivalent seasonal influenza vaccine (15g of hemagglutinin per strain) or placebo (phosphate-buffered saline). Subjects were monitored for adverse events through a clinical history and physical examination, and blood was taken for testing at screening and on day 8 to assess vaccine safety. Serum samples obtained before and 21days after immunization were tested for influenza antibody titers using hemagglutination-inhibition (HAI) and microneutralization (MN) tests. No serious adverse events were reported. Pain and tenderness at the injection site were the most commonly reported symptoms in both vaccine and placebo groups. Overall, serum HAI responses of fourfold or greater magnitude were observed to H1, H3, and B antigen in 80%, 75%, and 70% of subjects, respectively. Seroprotection rates as measured by HAI were also high (100%, 100% and 86.67%, respectively, for H1, H3 and B). Thus, Torlak's seasonal trivalent influenza vaccine was not associated with adverse events, was well-tolerated and immunogenic. It should be further evaluated in clinical trials to provide sufficient safety and immunogenicity data for licensing in Serbia

Changes in the global hospitalisation burden of respiratory syncytial virus in young children during the COVID-19 pandemic: a systematic analysis

Background The coronavirus disease 2019 (COVID-19) pandemic was reported to have impacted RSV epidemiology and could have important implications for RSV prevention and control strategies. We aimed to understand the RSV-associated acute lower respiratory infection (ALRI) hospitalisation burden in children younger than five years during the COVID-19 pandemic period and the possible changes in RSV epidemiology from a global perspective.Methods We conducted a systematic literature search for studies published between January 1, 2020 and June 30, 2022, from MEDLINE (Ovid), Embase (Ovid), Global Health (Ovid), Web of Science, WHO COVID-19 database, CINAHL, LILACS, OpenGrey, CNKI, WanFang and ChongqingVIP. We included unpublished RSV epidemiology data shared by international collaborators. Eligible studies reported data for RSV-associated ALRI hospital admission rates or at least one of the following severity measures: the proportion of RSV cases that needed supplemental oxygen, mechanical ventilation or intensive care unit admission, and in-hospital case fatality ratio. A generalised linear mixed-effects model was used for data synthesis to understand the changes in the incidence, age distribution and severity of RSV-associated ALRI hospitalisations in children under five years during the COVID-19 pandemic, compared to the year 2019. Findings We included 61 studies, 14 studies from published literature and 47 unpublished datasets. Most studies (51/61) were from the high-income region, followed by the upper-middle-income region (9/61); only one study was from the lower-middle-income region, and no studies were from the low-income region. Compared to 2019, all income regions saw substantial decreases in RSV-associated ALRI hospitalisation rate across all age groups in 2020; the number of RSV-associated ALRI hospitalisations in children aged 0–&lt;60 months decreased by approximately 80% (325,000 to 66,000), 14% (581,000 to 501,000) and 42% (1,378,000 to 795,000) for high-income, upper-middle-income and lower-middle-income countries, respectively. RSV hospitalisation rate started to rise in 2021, and by March 2022, the annualised rate returned to a level comparable to 2019 (6·0/1000, 95% uncertainty interval [UI] 5·4–6·8 by March 2022 vs 5·0/1000, 3·6–6·8 in 2019) in high-income countries while remaining lower in middle-income countries. Across all time periods and income regions, RSV-associated ALRI hospitalisation rates peaked in infants aged 0–&lt;3 months and declined with increasing age. Compared to the pre-pandemic period, there was a significantly increased proportion of RSV-associated ALRI hospitalisations in those aged 12–&lt;24 months in high-income and upper-middle-income regions (ORs ranged from 1·30 [1·07–1·59] to 2·05 [1·66–2·54]). No consistent changes in disease severity were observed. Interpretation Our study documented a significant reduction in RSV-associated ALRI hospitalisation burden in children under five years during the first year of the COVID-19 pandemic. A rebound to pre-pandemic levels in RSV-associated ALRI hospitalisation rate was observed in the high-income region by March 2022 but not in the middle-income region, suggesting a more persistent negative impact of the COVID-19 pandemic on health-care systems and health-care access in middle-income regions. RSV surveillance needs to be established (or re-established) to monitor the changes in RSV epidemiology, particularly in low- and lower-middle-income countries.Funding EU Innovative Medicines Initiative Preparing for RSV Immunisation and Surveillance in Europe (PROMISE); Bill &amp; Melinda Gates Foundation; World Health Organization. <br/

WHO preferred product characteristics for monoclonal antibodies for passive immunization against respiratory syncytial virus (RSV) disease in infants - Key considerations for global use.

World Health Organization (WHO) preferred product characteristics describe preferences for product attributes that would help optimize value and use to address global public health needs, with a particular focus on low- and middle-income countries. Having previously published preferred product characteristics for both maternal and paediatric respiratory syncytial virus (RSV) vaccines, WHO recently published preferred product characteristics for monoclonal antibodies to prevent severe RSV disease in infants. This article summarizes the key attributes from the preferred product characteristics and discusses key considerations for future access and use of preventive RSV monoclonal antibodies

Safety and immunogenicity of a seasonal trivalent inactivated split influenza vaccine: a double blind, phase III randomized clinical trial in healthy Serbian adults

This study was a phase III, multicenter, double-blind, randomized, placebo-controlled trial to evaluate the safety and immunogenicity of a seasonal trivalent split, inactivated influenza vaccine (TIV) in healthy Serbian adults between the ages of 18 and 65 years. This egg-based vaccine was manufactured by the Institute of Virology, Vaccines and Sera, Torlak, Belgrade, Serbia. A total of 480 participants were assigned randomly in a ratio of 2:1 to receive a single intramuscular dose (0.5 ml) of the vaccine (15 µg of hemagglutinin per strain) or placebo (phosphate-buffered saline). Participants were monitored for safety, including solicited and unsolicited adverse events (AEs) and serious adverse events (SAEs). No SAEs related to vaccination were reported. Injection site pain (51.3%), injection site tenderness (40.4%), tiredness (17.0%), and headache (15.1%) were the most commonly reported solicited events in the vaccine group. Incidence of related unsolicited AEs was low (1.3%) among vaccinees. Hemagglutinin inhibition (HAI) titers were measured before and 21 days after vaccination in 151 participants. Overall, HAI seroconversion rates to H1 and H3 were observed in 90.1% and 76.2% of vaccinees, respectively. For B antigen, it was 51.5%, likely due to high pre-vaccination titers. Post-vaccination seroprotection rates were in the range of 78.2–95.0% for the three antigens. Post-vaccination geometric mean titers (GMT) were at least 3.8 times higher than baseline levels for all the three strains among vaccinees. Overall, the study showed that the vaccine was safe and well tolerated, and induced a robust immune response against all three vaccine strains., ClinicalTrials.gov identifier: NCT02935192, October 17, 201

Monoclonal antibodies and vaccines against infectious diseases: Influenza, rabies and respiratory syncytial virus

Monoclonal antibodies (mAbs) have been used extensively for treatment of some cancers and chronic diseases for over three decades. However, their use in infectious diseases has been limited, partially due to their high production costs and limited duration of protection. Nonetheless, mAbs may have niche applications in the control of infectious diseases in the absence of or in conjunction with vaccines to address unmet public health needs. The research I conducted for this thesis began with a review of infectious disease mAbs in clinical development, before seeking to evaluate how mAbs could be used in the control of infectious diseases, focusing on replacing blood-derived immunoglobulins, pandemic preparedness and addressing gaps in prevention where vaccine development has been challenging. These areas were explored in the context of prevention and control of rabies, influenza, and RSV. For rabies, I undertook a review of mAb candidates in clinical development to inform decisions at WHO on inclusion of mAbs in global policy recommendations for rabies post-exposure prophylaxis (PEP). These findings supported decisions to include mAbs in rabies PEP recommendations and the Essential Medicines Lists as alternatives to blood-derived immunoglobulins. For influenza, I looked at both global vaccine production and development of influenza mAbs, in the context of pandemic preparedness. New estimates of global vaccine production were produced through a survey administered to manufacturers, supplemented by a review. I estimated that initial production capacity would be insufficient for global needs and, given delays in initial availability, alternative interventions will be required early in a pandemic. I also reviewed the development of influenza mAbs leading to their inclusion as a research target in the Global Influenza Strategy. For RSV, a disease where vaccine development has been challenging, this research sought to estimate whether long-acting mAbs could potentially be a cost-effective strategy for RSV prevention in Australian infants. The study estimated that, depending on the assumed price, RSV mAbs could be cost-effective. The research also contributed to the development of WHO preferred product characteristics for RSV mAbs. Collectively these studies demonstrate the potential for an expanded role of mAbs in the prevention and control of infectious diseases

Rationale for vaccination with trivalent or quadrivalent live attenuated influenza vaccines: Protective vaccine efficacy in the ferret model.

Background and aimThe majority of seasonal influenza vaccines are trivalent, containing two A virus strains (H1N1 and H3N2) and one B virus strain. The co-circulation of two distinct lineages of B viruses can lead to mismatch between the influenza B virus strain recommended for the trivalent seasonal vaccine and the circulating B virus. This has led some manufacturers to produce quadrivalent influenza vaccines containing one strain from each B lineage in addition to H1N1 and H3N2 strains. However, it is also important to know whether vaccines containing a single influenza B strain can provide cross-protectivity against viruses of the antigenically distinct lineage. The aim of this study was to assess in naïve ferrets the potential cross-protective activity of trivalent live attenuated influenza vaccine (T-LAIV) against challenge with a heterologous wild-type influenza B virus belonging to the genetically different lineage and to compare this activity with effectiveness of quadrivalent LAIV (Q-LAIV) in the ferret model.Methods and resultsFerrets were vaccinated with either one dose of trivalent LAIV containing B/Victoria or B/Yamagata lineage virus, or quadrivalent LAIV (containing both B lineages), or placebo. They were then challenged with B/Victoria or B/Yamagata lineage wild-type virus 28 days after vaccination. The ferrets were monitored for clinical signs and morbidity. Nasal swabs and lung tissue samples were analyzed for the presence of challenge virus. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay. All LAIVs tested were found to be safe and effective against wild-type influenza B viruses based on clinical signs, and virological and histological data. The absence of interference between vaccine strains in trivalent and quadrivalent vaccine formulations was confirmed. Trivalent LAIVs were shown to have the potential to be cross-protective against infection with genetically different influenza B/Victoria and B/Yamagata lineages.ConclusionsIn this ferret model, quadrivalent vaccine provided higher protection to challenge against both B/Victoria and B/Yamagata lineage viruses. However, T-LAIV provided some cross-protection in the case of a mismatch between circulating and vaccine type B strains. Notably, B/Victoria-based T-LAIV was more protective compared to B/Yamagata-based T-LAIV