Since 19 February 2013, the WHO has reported more than 130 laboratory-con-firmed human cases (37 fatal) of a novel avian influenza A(H7N9) across northern China. While human to human transmis-sion so far appears extremely limited and non-sustained, it is prudent to recognize the pandemic potential of A(H7N9) and consider preparedness and response arrangements, a key component of which is consideration of the use of pandemic or prepandemic vaccines.
Summary of the A(H7N9) situationOn 31 March 2013, the Chinese national authorities notified WHO of three con-firmed human cases of novel low patho-genic avian influenza A(H7N9). The cases came from Shanghai and Anhui Province in northern China and were not epidemio-logically linked [1]. Further cases have con-tinued to be confirmed and at the time of writing (3 July 2013) the total reported by WHO has reached 132 cases, including 37 fatalities. To date all but one of the cases have occurred in northern China [2], with one fatal case in Taiwan associated with travel to China [3].
Epidemiological investigation has identified that the majority of cases are middle-aged or elderly men from urban environments. Exposure to poultry has been reported in approximately 60% of
cases. Patients typically develop severe illness, with symptoms of influenza-like illness, and signs of acute respiratory dis-tress syndrome and viral pneumonia. The extent of mild and asymptomatic cases of A(H7N9) appears to be negligible at pre-sent. Extensive contact tracing has been undertaken but other than a few small familial clusters there is currently no sug-gestion of sustained human to human transmission. This epidemiological situ-ation offers little reassurance and could change quite rapidly [4–6].
The animal reservoir of the virus is yet to be identified; however, various avian species have been suggested [7,8]. The Chinese authorities have undertaken prompt action in response to the detection of human cases, including closing bird markets, and the sharing of viral isolates and epidemiological data.
Since the SARS outbreak in 2003 and the A(H1N1) pandemic in 2009–2010, it is widely recognized that a novel transmis-sible respiratory virus cannot be contained at source. Although the number of reported new cases of A(H7N9) has reduced sig-nificantly since early May 2013, the global health community continues to monitor the situation and consider a range of clini-cal and nonclinical countermeasures and options to prevent further deterioration in the epidemiological situation [9].
Preparing for a potential A(H7N9) pandemic: lessons from the deployment of A(H1N1) pandemic vaccinesExpert Rev. Vaccines 12(8), 825–828 (2013)
“The emergence of influenza A(H7N9) as separate but highly credible pandemic threat in early 2013 highlights the difficulty of selecting prepandemic vaccines by influenza A subtype, but
also the potential value of holding some form of ‘insurance’ against a range of ‘most likely’ pandemic threats.”
Jonathan S Nguyen-Van-TamHealth Protection & Influenza Research Group (WHO Collaborating Centre for Pandemic Influenza & Research), Division of Epidemiology & Public Health University of Nottingham Medical School, City Hospital, Nottingham, NG5 1PB, UK [email protected]
Chloe SellwoodPandemic Influenza Resilience Manager & Horizon Scanning Lead, NHS England (London), Southside, 105 Victoria Street, London, SW1E 6QT, UK
Use of vaccines in response to previous pandemicsIn order to understand the potential role of vaccines in the present A(H7N9) crisis, it is instructive to consider the legacy of both the 20th century and the recent 2009–2010 A(H1N1) pandemic. The first pandemic deployment of human influenza vaccines was in 1957 in the USA and UK in response to influenza A(H2N2). However the vaccine was available too late and in too short sup-ply to make a meaningful contribution to pandemic response [10], a situation repeated in the 1968 A(H3N2) pandemic, although vaccine was slightly more widely available. It was only after the emergence of a novel A(H1N1) ‘swine flu’ among military per-sonnel at Fort Dix (NJ, USA) in 1976 that the concept of mass vaccination against a pandemic threat truly emerged. In response to this incident 25% of the US population (>40 million persons) were vaccinated; but the program was halted due to the emer-gence of an excess number of cases of Guillain–Barré syndrome temporally associated with vaccination [11].
The establishment of avian influenza A(H5N1) as a potent pandemic threat led health policy makers to consider how the difficulties of the past could be overcome to ensure speedier and more widespread future access to pandemic influenza vaccines. Global (seasonal) influenza vaccine manufacturing capacity in 2003 stood at 350 million doses per annum, contrasted against the need to vaccinate more than 7 billion people during a severe pandemic (each potentially requiring two doses of vaccine); and a manufacturing cycle of 8 months from WHO strain selection, to delivery of commercial lots [12].
Prepandemic vaccinationThe concept of prepandemic vaccination emerged around 2006 and was predicated on the notion that if manufacturing capacity is limited and lead time too great, provided that pandemic threats can be ‘spotted’ well in advance, then vaccine against a potential future threat could be stockpiled, to be rapidly deployed when a crisis emerges. Between 2007 and 2009, several countries pursued this approach, aiming to cover a proportion of their population against the threat of A(H5N1) [13]. This strategy appeared to have been unsuccessful when influenza A(H1N1)pdm09 emerged as the first pandemic virus of the 21st century in early 2009; how-ever, it is still not possible to disregard the possibility of a future A(H5N1) pandemic and it might yet be judged worthwhile. The emergence of influenza A(H7N9) as a separate but highly cred-ible pandemic threat in early 2013 highlights the difficulty of selecting prepandemic vaccines by influenza A subtype, but also the potential value of holding some form of ‘insurance’ against a range of ‘most likely’ pandemic threats.
Antigenic sparing Faced with the likely scale of demand for a pandemic-specific vaccine, and evidence that two doses of vaccine might be required
to achieve seroprotection with A(H5N1) vaccines, manufacturers sought solutions that would eke out the available antigen, allowing a greater number of individuals to be vaccinated from a limited manufacturing base. These strategies were pursued successfully in the 2009–2010 pandemic using proprietary oil-in-water adju-vants. An important variation of the adjuvant concept is to stock-pile an adjuvant separately for later mixing with the antigen [14].
Increased production capacity & rapid licensure pathwaysIt became rapidly clear in 2003 that global influenza vaccine manufacturing capacity fell far short of potential pandemic needs. Yet for almost all manufacturers, an economic reality linked production capacity to annual demand for seasonal vac-cines [15]. The WHO Global Action Plan for Influenza Vaccines was instrumental in raising global capacity to 900 million tri-valent vaccine doses by early 2009, equivalent to 2.7 billion doses of monovalent vaccine; and up to 4.7 billion doses by mid 2009. These included novel manufacturing processes that use cell culture to obviate the historical reliance on eggs [16]. There have also been developments in regulatory procedures allow-ing ‘mock-up’ pandemic vaccine prototypes to be prelicensed so that final regulatory approval can be achieved in days or weeks, not months. Even so, pandemic vaccines became available from late September 2009, with gradual delivery over several months. This was too late in many countries of the northern hemisphere, where activity mainly peaked in early autumn 2009. Public health authorities should fund clinical trials of A(H7N9) vaccines as soon as possible since this is an avoidable poten-tial ‘bottleneck’. Linked to this, is a need to ensure that, if the epidemiological situation deteriorates, any signal from WHO to recommend switching from seasonal vaccine production to A(H7N9) vaccine production is more expedient than in 2009.
Procurement & logisticsIn general, prior to the 2009–2010 pandemic, attention was focused on vaccine production capacity and rapid licensure, rather than on the practical aspects of global distribution, logistics and communication. In these areas, the 2009–2010 pandemic vac-cination programmes were rather less successful and lessons have been identified but not yet learned.
Many models of vaccine procurement were followed before and during the 2009–2010 pandemic, including advanced purchase agreements that afforded priority or group purchasing arrange-ments. Ninety seven low-income countries relied on WHO-donated stock and supplies that only began in January 2010; which was largely too late to be meaningful. Internally, many countries faced partially unforeseen issues related to: distribu-tion points; movement logistics; cold chain storage; consumables (needles and syringes) and staffing arrangements [12].
“…many countries faced partially unforeseen issues related to: distribution points; movement logistics;
cold chain storage; consumables (needles and syringes) and staffing arrangements.”
“Public health authorities should fund clinical trials of A(H7N9) vaccines as soon as possible since this is
an avoidable potential ‘bottleneck’.”
826 Expert Rev. Vaccines 12(8), (2013)
Nguyen-Van-Tam & Sellwood
Editorial
Public acceptance & vaccine safetyParadoxically, although obtaining adequate and timely supplies of vaccine had been a major preoccupation in many countries, the tim-ing of availability coupled with a growing awareness that A(H1N1)pdm09 had produced a mild pandemic led to underdemand for vaccine by the public and in many cases unused stock. Problems were encountered in terms of how governments communicated the benefits of vaccination to their citizens [12]. Despite the legacy of a potential association of A(H1N1) vaccines and Guillain–Barré syndrome, no strong association was apparent in 2009–2010 [17]. Instead, use of AS03-adjuvanted pandemic A(H1N1) vaccines has been potentially associated with narcolepsy in children; this is still under investigation by the European Medicines Agency [18].
ConclusionThe legacy of unsuccessful use of pandemic vaccines in the 20th century has been largely overcome by preparations for a possible influenza A(H5N1) pandemic and the practical experience of mass production and deployment of A(H1N1)pdm09 vaccines in 2009–2010. In the light of the current A(H7N9) threat, the options for preparation and use of vaccine in the public health response are greater than at any previous time. Notwithstanding, old and potentially insolvable problems persist, such as time of availability of vaccines in relation to the rapid spread of a novel virus, risk communication with the public and the lack of global equity in vaccine distribution. Until our dependence on subtype-specific
vaccines is broken by the introduction of novel vaccines targeting conserved antigens, or based on T-cell responses, these problems are likely to persist.
DisclaimerThe views represented in this article are those of the authors and not necessarily the official views of Public Health England, the University of Nottingham, the WHO or NHS England.
Financial & competing interests disclosureBetween September 2007 and September 2010, JS Nguyen-Van-Tam under-took paid speaker engagements and consultancy for the following influenza vaccine manufacturers: Baxter AG, GlaxoSmithKline, Novartis, Sanofi-Pasteur MSD and Solvay. He is a former employee of SmithKline Beecham plc (now part of GlaxoSmithKline) and Aventis-Pasteur MSD (now Sanofi-Pasteur MSD), both prior to 2005, but holds no interests in these or any other influenza vaccine manufacturers by way of share holdings, share options or accrued pension rights. His unit receives or has recently received research funding from GlaxoSmithKline and Astra-Zeneca. Since October 2010 his unit has been a WHO Collaborating Centre for pandemic influenza and research. C Sellwood undertook paid speaker engagements for Baxter AG in 2011. The authors have no other relevant affiliations or financial involve-ment with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
ReferencesPapers of special note have bee highlighted as:• of interest
•• of considerable interest
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