key: cord-1056147-mjij7dgs
authors: Ankomah, Alex Asamoah; Moa, Aye; Chughtai, Abrar Ahmad
title: THE LONG ROAD OF PANDEMIC VACCINE DEVELOPMENT TO ROLLOUT: A SYSTEMATIC REVIEW ON THE LESSONS LEARNT FROM THE 2009 H1N1 INFLUENZA PANDEMIC
date: 2022-02-04
journal: Am J Infect Control
DOI: 10.1016/j.ajic.2022.01.026
sha: bd6b4acfd76516680bf71907670854f61345cbd0
doc_id: 1056147
cord_uid: mjij7dgs

BACKGROUND: The 2009 Influenza A(H1N1) pandemic prompted one of the largest public health responses in history. The continuous emergence of new and deadly pathogens has highlighted the need to reflect upon past experiences to improve pandemic preparedness. The aim of this study was to examine the development and rollout of 2009 influenza A(H1N1) pandemic vaccine and knowledge challenges for the effective implementation of vaccination programs for COVID-19 and future influenza pandemics. METHODS: A systematic review was conducted searching EMBASE (inception to current date) and PUBMED (from January 2009 to current date) databases for relevant published studies about influenza A(H1N1) pandemic vaccines. A Google search was conducted to identify relevant documents from grey literature. Selected Studies were reviewed and summarized. RESULTS: A total of 22, comprising of 12 original studies and 10 relevant documents met the inclusion criteria. Fourteen papers reported an initial high demand that outweighed production capacity and caused vaccine shortages. Vaccine procurement and supply were skewed towards high-income countries. Low vaccination rates of about 5% to 50% were reported in all studies mainly due to a low-risk perception of getting infected, safety concerns and the fear of adverse effects. CONCLUSION: Safety concerns about the approved H1N1 vaccines resulted in many unsuccessful vaccination campaigns worldwide. Understanding the factors that influence people's decision to accept or refuse vaccination, effective risk communication strategies, adequate resources for vaccine deployment initiatives and building local capacities through shared knowledge and technology transfer may help to improve COVID-19 vaccine uptake and accelerate pandemic control.

The 2009 Influenza A(H1N1) pandemic prompted one of the largest public health responses in history. The continuous emergence of new and deadly pathogens has highlighted the need to reflect upon past experiences to improve pandemic preparedness. The aim of this study was to examine the development and rollout of 2009 influenza A(H1N1) pandemic vaccine and knowledge challenges for the effective implementation of vaccination programs for COVID-19 and future influenza pandemics.

A systematic review was conducted searching EMBASE (inception to current date) and PUBMED (from January 2009 to current date) databases for relevant published studies about influenza A(H1N1) pandemic vaccines. A Google search was conducted to identify relevant documents from grey literature. Selected Studies were reviewed and summarized.

A total of 22, comprising of 12 original studies and 10 relevant documents met the inclusion criteria. Fourteen papers reported an initial high demand that outweighed production capacity and caused vaccine shortages. Vaccine procurement and supply were skewed towards highincome countries. Low vaccination rates of about 5% to 50% were reported in all studies mainly due to a low-risk perception of getting infected, safety concerns and the fear of adverse effects.

Safety concerns about the approved H1N1 vaccines resulted in many unsuccessful vaccination campaigns worldwide. Understanding the factors that influence people's decision to accept or refuse vaccination, effective risk communication strategies, adequate resources for vaccine deployment initiatives and building local capacities through shared knowledge and technology transfer may help to improve COVID-19 vaccine uptake and accelerate pandemic control.

Keywords: Pandemic influenza, H1N1 vaccine, vaccine development, COVID-19 vaccine, vaccination, pandemic preparedness Background Traditionally, vaccine development is an extensive, long, and expensive process with no assurance of success despite the significant financial and human resources utilized. 1 In past, vaccine development for epidemics -severe acute respiratory syndrome coronavirus (SARS-CoV), Ebola virus and Zika virus were only completed during the post-pandemic phase thereby causing huge financial loss to manufacturers, wastage of allocated funds by countries and a significant setback of other relevant vaccine development programs. 2 With COVID-19, the urgency emanating from the increasing trends in morbidity and mortality has led to significant changes in already established timelines among vaccine developers so as to provide successful candidates to the world as quickly as possible. At least seven vaccines across three distinct platforms have currently received approval for emergency use and rolled out in many countries. 3 The World Health organization (WHO) reports an additional 200 candidates in development with about 76 in different clinical phases of development globally over the past year. 4 Most countries are initially targeting vulnerable groups for vaccination. 5 However, there still exists many unresolved concerns with these approved vaccines such as the possible appearance of variant strains resistant to the current vaccines. Additionally, technical challenges in building the capacity for the production of billion doses of vaccines and ethical concerns associated with the provision of vaccines to poor countries remain an imminent challenge. 3 Although there have been multiple previous influenza pandemics, experts were faced with similar new experiences in 2009 as a result of the emergence of a novel H1N1 virus. 6 New COVID-19 vaccines have been developed and rolled-out in a relatively short period of time.

Despite many controversial discussions and public concerns on these approved vaccines, it is observed that most of the global focus is on developing and/or improving newer, experimental approaches to aid in vaccine development within the shortest possible time.

There is limited attention among the scientific community, manufacturers and other stakeholders on the lessons that can be learnt from past epidemics/pandemics to inform current and future vaccine research, development and rollout. 7 This review aimed to examine vaccine development and rollout during the 2009 Influenza A(H1N1) pandemic to gain a better understanding of the experiences encountered and to highlight specific lessons learned from this past pandemic to support current COVID-19 vaccination programs as well as future pandemics.

A systematic review was conducted adhering to the guidelines on Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). 8 Two main search strategies were employed. First, the systematic search to identify relevant peer-reviewed articles was conducted using: EMBASE (since inception to current date) and PUBMED (from January 2009 to current date). Primary studies providing original quantitative and/or qualitative data on the 2009 Influenza A H1N1 pandemic vaccine development and rollout were sought during the search. Although the WHO from October 2011 recommends the use of influenza A(H1N1)pdm09 as a standardized nomenclature, a broad search strategy was adopted to identify all relevant articles in which 2009 H1N1 pandemic vaccines were described and relevant to the areas of discussion in this review since other names were used prior to WHO recommendation. 9 The EMBASSE search terms used included: subject headings '2009 H1N1 influenza' OR '2009 adj4 (H1N1 or influenza or flu or pandemic)' OR '2009 adj4 (swine flu or swine influenza or swine-origin)' AND 'vaccin* adj4 (implementation or uptake or rollout or rollout) '  Studies on multiple influenza strains that reported specific (non-aggregate) data on H1N1 pandemic vaccines or vaccination.

 Studies describing intentions or willingness to receive H1N1 vaccines or institutional capability and willingness to produce H1N1 vaccines prior to, during or after the pandemic phase with no data on the actual R&D process or pandemic vaccination activities.

 Secondary data sources.  Immunogenicity, safety or clinical efficacy of H1N1 vaccines.

 Unrepresentative/small study samples such as case series/reports, editorials, letters and opinion papers

The identified articles and grey literature were exported into Endnote X9. Both reviewers independently screened articles by titles and abstracts to identify relevant papers for full review. Potentially relevant articles were read by both reviewers independently to determine the final selection of relevant articles for inclusion. For grey literature, all first six pages in Google were similarly screened in three stages: title, abstract (when available) and full-text screening against the eligibility criteria. The detailed selection process used in the study is outlined in the PRISMA flow diagram in figure 1. Data extracted for each article included the author/study year, study design or any theoretical model employed, study size, data collection methods including time periods, study participants, and the study outcomes. The data extracted from relevant grey literature included the author/ study year, institution involved, aims and objectives of the report and the outcomes reported. The eligibility criteria and template for extraction were adhered to strictly by both reviewers to ensure consistency. All findings including discrepancies were discussed among all reviewers to arrive at the final selection. 

Three papers reported that active manufacturing processes to produce the monovalent H1N1 influenza pandemic vaccines were conducted by the same influenza vaccine companies that produce seasonal influenza vaccines in the USA, Australia, China, Russia, India and the European Union. 1, 10, 11 Also, one reports that new manufacturers contributed to vaccine development in some Asian countries including Japan and Korea Republic. 10 Three papers indicated that alongside the traditional approach of production with chicken eggs, a new culture biotechnology was used in the manufacture of cell-derived pandemic vaccines which were also distributed to many countries during the pandemic. 1, 11, 12 Five papers mentioned the development and approval of four vaccines in the US and European Union countries. 1, [11] [12] [13] [14] However, the CDC also reported a fifth pandemic vaccine that was also approved by the Food and Drugs Administration (FDA) in the US two months after approval of the initial four vaccines. 13 In the United Kingdom, two pandemic vaccines namely Pandemrix (GlaxoSmithKline) and Celvapan (Baxter) were initially approved for use in a one dose and two dose-schedule, respectively. 14 

According to twelve papers, implementation of vaccination varied greatly among nations and were implemented mainly by General Practitioners, Primary healthcare providers, public health authorities and other services like the Red Cross. 10, [15] [16] [17] [20] [21] The roll-out of vaccines during the 2009 pandemic was characterized by an initial increase in the demand for vaccines by nations but declined as the pandemic progressed. 13 Three papers reported that most countries opted for a single dose for adults instead of the two-dose schedule in order to vaccinate more people and procured multi-dose vials to prevent further delays. 13, 15, 17 Five reported that national vaccination coverages were low and ranged averagely from 5% in WHO-assisted countries to about 50% in the UK and Sweden. 1, 11, 14, 19, 22 Four papers reported low vaccination coverage among pregnant women and healthcare workers who were highrisk groups and targeted for vaccination. Vaccine coverage for pregnant women was 6.2% in Hong Kong 16 and median coverage of 21% in WHO-assisted African countries 18 whiles that of heathcare workers was 28.2% in Saudi Arabia 23 , 17% in Italy 24 ,and median covergae of 9% in WHO-assisted African countries. 18 Nine reported that globally, the refusal of vaccines was mainly due to the fear of side effects, poor or no counselling from healthcare providers and a common perception that vaccines were unnecessary due to the mild clinical nature of the infection. 14, 16, [22] [23] [24] [25] In Morocco, belief in pandemic conspiracies were also rife. 26 In the UK and Singapore where uptake was relatively higher (35-45%), vaccine acceptability was Therefore, there is a need to critically consider and understand these factors that influence an individual's decision to either accept or refuse vaccination in order to mount a successful vaccination program.

A lesson learnt is that although purchasing agreements reduce the complex and timeconsuming negotiations that will otherwise occur during emergency situations, these direct agreements that may occur before or at the initial stages of a pandemic contribute significantly to the persistent inequitable vaccine distribution between rich and poor countries during pandemics. In 2009, challenges with vaccine supply were widespread and mostly affecting countries with very limited access to the approved vaccines. 28 Most of the manufacturing capacity had been procured by wealthier nations through direct pre-existing agreements with manufacturers such that, vaccines were scarce for countries that had no contracts with developers. 29 More than a decade after, equitable vaccine access and supply remains a major topic of discussion even in the current COVID-19 pandemic suggesting that this lesson from 2009 may have been ignored. Current data shows that wealthier countries representing only 14% of the world population have already secured 53% of the leading COVID-19 vaccine candidates both approved and in clinical trials such that they are able to vaccinate their total population by three to five times over by 2021. 30 As such, we are currently experiencing an unequal supply and rollout of COVID-19 vaccines worldwide with recent shortages in many low-resourced countries that continue to face high COVID-19 morbidity and mortality. Pre-pandemic purchasing agreements were not in place (or possible)

for COVID-19 as this was a completely novel virus, however, many direct agreements have already been made such that low-income countries are unable to secure additional vaccines in a timely manner despite international support from vaccine deployment initiatives. Rather having to secure two vaccine doses per person. Additionally, this single-shot vaccine is stable and can be kept at refrigerator temperature thereby minimizing challenges with cold storage in these low-resource settings. 5 Collaborated efforts are further needed to streamline the long bureaucratic processes associated with vaccine donations to poorer countries to improve timeliness and promote equitable access to pandemic vaccines in current and future pandemics. Furthermore, the recognition of regulatory and approval mechanisms between countries will minimize the barriers associated with licensing and supply of approved vaccines.

We also learn that emerging technologies arising from long-standing influenza vaccine R&D Similarly, messenger (mRNA) vaccine technology has been researched extensively for many decades in many viruses to improve industry expertise in this area. 5 The onset of the COVID- 33 However, vaccine hesitancy still remains a major concern. Reasons for vaccine refusal given in 2009 have been identified as threat to current COVID-19 vaccination targets with many, including health professionals sharing safety concerns and also questioning the speed of development of the vaccines. 34 Therefore, urgent collaborations with relevant stakeholders such as the media and healthcare professionals should be undertaken to improve knowledge among these stakeholders on the available vaccines and help in the dissemination of right information to the public. Additionally, vaccine implementation activities should be adapted to suit the sociocultural, economic, and political contexts of a country to achieve pandemic control.

This is the first review to our knowledge that comprehensively examines available literature on the 2009 Influenza A(H1N1) pandemic from vaccine development to the rollout and uptake of vaccines. It highlighted important aspects that may have been ignored but useful to improve the current COVID-19 response and offers guidance as part of pandemic preparedness for future responses. Several limitations are present in this study. Comparing these two viruses might be flawed in that, the processes for developing these vaccines differed greatly as influenza vaccine development has longstanding production methods that can easily be utilized for new influenza pandemic strains, versus a completely novel coronavirus. The evidence presented does not cover all countries that manufactured H1N1 vaccines and implemented vaccination campaigns. Although these limitations are present, the 2009 findings were consistent from different regions and countries included in the study and as such, the lessons learnt from the past pandemic are valuable for informing the current COVID-19 pandemic and future pandemics.

There was limited data obtained from lower-and middle-income countries (LMIC) on the 2009 H1N1 pandemic vaccine rollout and uptake which would have provided extra valuable information on experiences faced in poor countries during pandemics. This paucity of evidence available from LMIC emphasizes the need for further research to strengthen the current evidence available.

The rapid development of vaccines during the 2009 H1N1 pandemic using both existing eggbased and novel cell culture-derived technology demonstrates the significant advancements in vaccine research and development. However, the inequitable distribution of vaccines coupled with inadequate manufacturing capacity to meet global demands led to an initial scarcity of approved vaccines in many poor countries and subsequently, a low uptake of approved vaccines due to safety concerns and fear of adverse effects. More than a decade after, similar events of inequitable distribution and scarcity of vaccines in developing countries are being experienced in the current COVID-19 pandemic and continues to threaten a high uptake of COVID-19 vaccines. Therefore, global and regional collaborative efforts aimed at knowledge and technology transfer, prioritizing COVAX support and stronger policies are urgently needed to increase production capacity and support the equitable distribution of vaccines which is essential for pandemic control in the shortest possible time.

Role of authors -AAA and AC conceived the idea of the study and conducted the study.

AAA drafted the manuscript. AM and AC contributed to the writing of the manuscript and final submission.

This research did not receive any specific funding

Not applicable

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Authors declare no competing interests and have no non-financial interests that may be relevant to the submitted work.