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Considerations for the rapid deployment of vaccines against H7N9 influenza Expert Review of Vaccines Downloaded from informahealthcare.com by Korea University on 01/06/15 For personal use only.

Expert Rev. Vaccines 13(11), 1327–1337 (2014)

Brendon Y Chua*, Lorena E Brown and David C Jackson Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia *Author for correspondence: Tel.: +61 390 353 129 [email protected]

The threat of an outbreak of avian-origin influenza H7N9 and the devastating consequences that a pandemic could have on global population health and economies has mobilized programs of constant surveillance and the implementation of preemptive plans. Central to these plans is the production of prepandemic vaccines that can be rapidly deployed to minimize disease severity and deaths resulting from such an occurrence. In this article, we review current H7N9 vaccine strategies in place and the available technologies and options that can help accelerate vaccine production and increase dose-sparing capabilities to provide enough vaccines to cover the population. We also present possible means of reducing disease impact during the critical period after an outbreak occurs before a strain matched vaccine becomes available and consider the use of existing stockpiles and seed strains of phylogenetically related subtypes, alternate vaccination regimes and vaccine forms that induce cross-reactive immunity. KEYWORDS: adjuvant • H7N9 • influenza • pandemic • vaccine

As of February 2014, a total of 375 laboratory-confirmed cases of human infection with avian influenza A H7N9 have been reported [1], mostly originating from 13 provinces and municipalities in mainland China and also from Hong Kong, Taiwan and Malaysia. The majority of these cases have occurred in two waves and appear to follow a seasonal pattern associated with cooler temperatures, with the peak of reported cases in the first wave occurring in March 2013 followed by a second wave beginning in January 2014. Infection with H7N9 has to date resulted in a mortality rate of approximately 30%. Complications arising from infection is typically characterized by acute respiratory distress syndrome, rapid progression to viral pneumonia, septic shock and multiorgan failure in severe cases [2–4]. Trace studies have so far found little evidence of sustained human-to-human transmission and although the source of infection is yet to be confirmed, the sequence analysis of viral isolates points to various avian species as reservoirs [5], with a high likelihood of infection associated with exposure to infected poultry or their contaminated environments. The dominance of severe infection with the H7N9 virus

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in males in the older age range (median age of 63 years) is yet to be explained [6]. As with other avian influenza viruses, H7N9 is resistant to M2-ion channel inhibitor-based antivirals such as amantadine due to the presence of a Ser31Asn substitution in the M2 protein [5]. This leaves the neuraminidase (NA) inhibitors zanamivir, oseltamivir and peramivir as the main treatment options. While early intervention with these antivirals can be effective in reducing severe illness and preventing death, the emergence of mutations conferring resistance to both zanamivir and oseltamivir [7–9] is a concern. Although the virus binds weakly to a2,6-linked sialic acids found predominantly on the cell surfaces of the human respiratory tract [10,11], amino acid substitutions in the viral hemagglutinin (HA) that appear to be associated with increased binding affinity for these sialic acids have been reported [5,12]. Other mutations have been identified that may permit the virus to replicate more efficiently in temperature ranges found in mammals facilitating transmission in animal models [5], highlighting its capacity to become readily transmissible between humans and its

 2014 Informa UK Ltd

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potential to cause a pandemic. In light of these various properties of H7N9, we discuss strategies that are in place and which are aimed at alleviating the severity of disease should isolated outbreaks become a pandemic.

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Pandemic preparedness

Vaccination using inactivated detergent split virus-based vaccines that induce HA- and, to a lesser extent, NA-specific neutralizing antibodies is an effective way to significantly reduce the mortality and morbidity rates caused by seasonal influenza. These vaccines are often reformulated every year or so to include the surface glycoproteins of two influenza A strains and one or both of the B strain lineages (in the trivalent and quadrivalent vaccines, respectively) that are predicted to circulate in the forthcoming influenza season. In addition, cold-adapted trivalent as well as quadrivalent live-attenuated influenza vaccines (LAIVs), discussed further below, are also used to provide coverage in several countries, including the USA and Russia. Based on experience gained since the emergence of human cases of highly pathogenic avian influenza H5N1 in 1997, a key priority for pandemic preparedness in a number of countries involves the stockpiling of vaccines. These vaccines, based on viral strains identified as potential pandemic threats, are prepared as a preemptive measure in anticipation of the long lead time to produce vaccines matched more closely to the emerging strain, and of the limited manufacturing capacity to produce sufficient vaccines for mass vaccination, if required [13]. It can, however, be difficult to know how closely matched these prepandemic vaccines will be to a novel subtype that does eventually arise but, nevertheless, even a poorly matched strain can presumably provide the vaccinee with a pool of memory B cells with the potential for hypermutation to produce appropriate antibodies rather than relying on activation of the naı¨ve B-cell repertoire, a much less efficient process. The unforeseen emergence of swine-derived H1N1 in 2009 and now H7N9 highlights the challenges associated with the prediction and selection of future strains for stockpiling; therefore, there is an ever-present need to develop counter measures that will supplement the protection afforded to global communities during the susceptible periods between the beginning of an outbreak and when a vaccine does become available. The existing seasonal trivalent vaccine manufacturing capacity (including live-attenuated and inactivated virus vaccines) for 2011 stands at 1420 million doses and present efforts to strengthen global vaccine production and access suggest that current vaccine production capacity could be increased threefold if a monovalent pandemic vaccine is needed [14]. This figure still falls well short of the amount of doses required to provide coverage for the world’s population and could be even further affected by low antigen yields produced by vaccine seed strains and the need to administer multiple doses. Several H7N9 seed strains, made mostly by reverse genetics using the HA and NA sequences of A/Shanghai/2/2013 and A/ Anhui/1/2013 strains, have been developed for vaccine production [15] and form the basis of H7N9 candidate vaccines that 1328

are currently being evaluated in clinical trials [16–23]. However, if results of previous human trials demonstrating varied immunogenicity induced by inactivated H7-based vaccines [24,25] are anything to go by, and given the lack of prevalent immunity to H7 strains in the population [26,27], the amount of antigen in a H7N9 vaccine needed to elicit protective immunity could be higher than anticipated and probably more than one dose would be required for adequate seroconversion. The key to addressing this shortfall can be achieved by increasing our existing vaccine manufacturing capabilities supplemented by new methods of vaccine production, the use of adjuvants to provide or improve dose-sparing, the development and introduction of cross-protective vaccine platforms and implementation of processes that can facilitate rapid authorization and distribution of pandemic vaccines. Strategies to increase pandemic vaccine manufacturing Cell culture-based vaccines

Embryonated eggs remain the highest yielding substrate for the production of the influenza vaccine, yet the concern that the availability of sufficient eggs for timely mass vaccination in a pandemic may be limited is one factor prompting the exploration of alternative substrates. Cell culture systems using Madin–Darby canine kidney [28], African green monkey kidney [29,30] and retinal human cell lines [31,32] have been evaluated for vaccine production and are now currently licensed for the manufacture of seasonal inactivated trivalent vaccines in the USA and several European countries [33–35]. Vaccines produced in cell culture have not only proven to be efficacious but also comparable with traditional egg-produced vaccines [35,36]. One of the major advantages of producing vaccines in cell culturebased systems is that the virus can be amplified without the appearance of egg-adaptive mutations in the HA that can alter the immunogenic properties of the vaccine. Such mutations have been particularly problematic for the H3N2 component of recent seasonal vaccines, rendering these a poor match with the wild-type virus [37,38] and their potential to influence other novel subtypes is unknown. The capacity to scale up cell culture vaccine production rapidly to provide shortened production times of as much as up to 10 weeks compared to vaccines produced in the traditional manner [39] has been claimed, but whether sufficient antigens can be produced in practice remains to be established. H5N1 whole virion-based vaccines produced using these culture systems have been found to be well tolerated and immunogenic [40] in healthy individuals [41], infants and children [42] as well as chronically ill and immunocompromised patients [42]. In some cases, induction of heterologous T-cell responses was also demonstrated [43]. Early preliminary reports from a Phase I clinical trial of an H7N9 cell culture-derived inactivated vaccine [17] have so far been positive and indicate protective immune responses in up to 78% of adult subjects vaccinated with two doses of the vaccine formulated with the proprietary MF59 adjuvant [23]. The results from this study highlight the need for adjuvants to improve the immunogenicity of H7N9 vaccines. They also Expert Rev. Vaccines 13(11), (2014)

Considerations for the rapid deployment of vaccines against H7N9 influenza

note that the use of a synthetic seed virus [44], derived from a virus rescued from cells transfected with plasmids encoding ‘backbone virus’ genes and genes encoding the appropriate HA and NA derived from synthetic fragments, could also be a critical factor for expediting global vaccine production as the time taken to derive high yielding viruses by ‘classical reassortment’ is negated.

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Live-attenuated influenza vaccines

Seasonal LAIVs produced in eggs through classical reassortment with cold-adapted master strains replicate only at the lower temperatures of the upper respiratory tract and offer some advantages over conventional inactivated vaccines. Comparative studies indicate that LAIVs are more effective than matched inactivated vaccines [45–47], although this does not appear to be the case in some seasons [45,48,49]. LAIVs, nonetheless, have been shown to induce a broader range of systemic and mucosal antibody as well as T-cell-mediated responses, which have been attributed to their ability to protect against drifted seasonal strains of the virus in humans [50,51], and is currently licensed for use in healthy individuals aged 2 through 49 years in the USA [52]. The use of a pandemic LAIV was first demonstrated against the H1N1 pandemic virus, A(H1N1)pdm09, where a single dose was safe and effective enough to induce immune responses against the homologous wild-type strain [53]. Protection against highly pathogenic strains has also been demonstrated in animals immunized with this vaccine [54] and with an H5N1 LAIV [55]. Several human clinical trials evaluating H7-based LAIVs [56–59], including H7N9 [16], have been completed or are still ongoing. These vaccines could presumably be efficacious if developed as pandemic vaccine strains to meet potential demand [60]. There is still, however, a perceived risk that LAIVs can potentially reassort with seasonal viruses, resulting in the formation of a virus containing the novel HA and the characteristics of a strain that can replicate and spread efficiently in the population. LAIV reassortment with circulating strains has been demonstrated experimentally and the results from these studies show that progeny reassortants are no less virulent than the attenuated strain [61,62]. Moreover, although reverse geneticsderived reassortants between live-attenuated H5N1 vaccine candidates and seasonal isolates have been demonstrated to be more virulent than their parent strains [40], reassortants recovered from H5N1 and H3N2 co-infection experiments using ferrets have been shown to replicate less efficiently than their parental strains and also lack transmissibility [63]. A potential strategy that could minimize the risk of reassortment takes advantage of the fact that reassortment between influenza types A and B viruses are not known to occur and therefore chimeric B viruses expressing modified influenza A HAs could be used as possible prepandemic vaccine strains because they will not be able to reassort with already existing circulating A strains of influenza [64]. This live-attenuated reassortant hybrid-type vaccine system could potentially be applied to incorporate different influenza A HAs, including H5, to induce protective homologous immunity. informahealthcare.com

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Various experimental approaches are nonetheless being explored to exploit the potential immunogenic benefits offered through LAIV use as a prepandemic priming vaccine. This approach involves the use of a prime-boost regimen [65–68] to induce memory responses using either existing subtype matched or mismatched LAIV vaccine strains or DNA during or before the early stages of a pandemic followed by a booster with a suboptimal dose of matched inactivated vaccine once available. Early results from these preliminary studies using H5N1 and H7N7 LAIVs indicate that this vaccination regime can lead to the induction of neutralizing antibodies against heterologous viruses ([69] and reviewed in [70]) and could be a practical way of providing short- and long-term protection during a pandemic, particularly when vaccine demand is high. Use of phylogenetically related seed strains

The previous outbreaks of avian-derived H7 strains [71], notably A/Netherlands/219/03 (H7N7), which resulted in 89 reported human cases in the Netherlands in 2003 [72,73], have led to the development of a number of H7 candidate vaccines that are currently being trialed as part of the WHO global influenza preparedness initiative [57,74,75]. While none of these strains contain N9 NA, the HAs are phylogenetically related to the HA of the H7N9 virus and there is evidence to suggest that existing stockpiles of vaccines produced from these seed strains could provide short-term protection in the event of an H7N9 pandemic. Experimental results have shown that sera from subjects vaccinated with some of these vaccine candidates cross-react with H7N9 [76] and that mice vaccinated with H7N3 and H7N1 vector-based [77] or inactivated [76] vaccines can be protected from challenge. Substantial antibody crossreactivity with H7N9 has also been reported using sera from ferrets [78] and humans [58,79] vaccinated with H7 LAIV strains containing mismatched NA. The added benefit of using these vaccines as an option to provide immediate coverage against H7N9 is that safety and toxicological assessments in humans would have been completed or at the very least currently in progress fast-tracking their implementation. Recombinant vaccines

The use of baculovirus expression systems to produce recombinant antigens in insect cells is a proven strategy for the manufacture of HA-based vaccines obviating the need to handle potentially pathogenic viruses (reviewed in [80]). Compared to other methods of vaccine manufacture, the versatility and strength in this system lies in its ability to rapidly produce large amounts of antigens. First licensed by the US FDA in 2013, the use of a trivalent recombinant HA seasonal vaccine (FluBlok) [81,82] has been reported to be safe and more immunogenic than traditional inactivated vaccines in adults [83] but not in young children [84]. Versions of this vaccine against H5N1 (PanBlok), which contains recombinant HA from A/Indonesia/5/05 or A/Vietnam/1203/2004, have since been reported to be well tolerated as well as being immunogenic [85,86]. This underlying manufacturing technology can be 1329

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rapidly adapted to produce vaccines against emerging strains within a short period of time and is best exemplified by the production of a virus-like particle-based vaccine candidate containing H7 and N9 from A/Anhui/1/13 within a month of its genomic sequence being made available. This was followed by its release for human use 2 months later [87]. Subsequent evaluations demonstrated that two doses of this vaccine administered in the presence of an adjuvant resulted in significant increases in neutralizing HA and NA-inhibiting antibody responses [88] in humans in addition to heterologous antibody responses against H7-related strains in mice [89]. Strategies currently being developed that could also be useful in the future include the use of gene-optimized H7-based DNA vaccines used to induce HA-specific T-cell responses [90] and HA stalk-based viral constructs that induce broadly neutralizing stalk-specific antibodies that cross-react with various HAs, including the H7 subtype [91,92]. Adjuvants

Recent immunoinformatics analyses performed by De Groot et al. [93,94] suggest that HAs of closely related H7N9 strains contain a lower number of identifiable T-cell epitopes compared to HAs from presently circulating influenza strains. This finding may in part account for the low immunogenicities observed with previous H7-based vaccines [93,94] trialed in both humans [24,31,95] and in animal models [25]. It is therefore likely that similar vaccines against H7N9 will either require higher amounts of antigens than that generally required for a seasonal vaccine to elicit protective immunity or that they be coadministered with an adjuvant. There are currently several ongoing and completed clinical trials evaluating the use of different adjuvants, including MF59 (Novartis), AS03 (GlaxoSmithKline) and Matrix-M (Novavax), formulated with subunit-based H7N9 vaccines [17–23]. Past H5N1 vaccine trials in humans have demonstrated that these adjuvants can improve the immunogenic potential of a pandemic vaccine, which in many ways justifies their inclusion in ongoing H7N9 candidate vaccine trials. MF59 has been shown to provide antigen dose-sparing [96] and improve the spectrum of protective immunity by increasing the range and affinity of antibodies induced against different H5N1 clades [97–99]. MF59 has also been reported to promote the activation of CD4+ T cells [100] and induce cross-clade immunity in young and elderly risk groups [96,101–103]. As mentioned earlier in this review, the use of MF59 has recently been demonstrated to significantly improve the antibody responses induced using a cell culturederived inactivated H7N9 vaccine [23]. The fact that less than 10% of subjects vaccinated with the nonadjuvanted vaccine had HI titers of >40 even after two doses supports the view that similar inactivated H7N9 vaccine forms will be poorly immunogenic in the absence of an adjuvant. Similar effects have also been demonstrated using AS03 where vaccine formulations are made more immunogenic in a wide range of subject types using what would otherwise be ineffective amounts of vaccine to induce cross-clade neutralizing 1330

antibody responses [104–107]. These antibodies can be maintained for up to 15 months [108] and are associated with strong B-cell and CD4 T-cell responses [109,110]. Furthermore, the induction and persistence of neutralizing antibodies can be obtained using as low as 1.9 mg of HA in young children with acceptable reactogenicity [111]. One of the newest adjuvants being evaluated in the H7N9 vaccine trials is Matrix-M. Clinical results have shown that both homologous and heterologous antibody responses can be induced when it is used with a virosomal-based H5N1 vaccine [112]. Furthermore, considerable dose-sparing down to 1.5 mg of HA has been demonstrated in association with the induction of strong Th1-type CD4+ T helper responses [113]. The ability of traditional alum-based adjuvants to improve existing vaccine strategies against H7N9 has not, however, been as clear. The ability of alum to enhance the immunogenicity of H5N1 vaccines varies, with some clinical trials reporting significant enhancement of antibody titers [31,114,115], while others indicating that it has no significant benefit on the ensuing immune responses [29,116–118], particularly at lower doses of the vaccine [119]. There is also a growing interest in other novel adjuvant systems, including agonists of toll-like receptors. While there are few reports on the use of these in influenza vaccines currently in clinical trials [120–123], it is worthwhile to note that totally synthetic, toll-like receptor agonist-based epitope-based experimental vaccines can protect mice from homologous and heterosubtypic virus challenge [124–127] and if administered intranasally in the absence of antigens can provide immediate protection against live virus challenge [128]. The importance of having suitable procedures in place for adverse reaction surveillance and reporting, particularly when new vaccine adjuvants are introduced, cannot be overemphasized. Despite the rarity of these events, incidences of narcolepsy reported in children and adolescents vaccinated with the European AS03-formulated A(H1N1)pdm09 vaccine raised major public concerns about the safety of adjuvants [129–131]. While the reasons for the cause of these events are yet to be elucidated, it has been noted that similar events have not been associated with the use of the Canadian AS03-formulated A (H1N1)pdm09 vaccine, leading to speculations that it could be attributed to differences in the vaccine antigen manufacturing/ inactivation process rather than the adjuvant (reviewed in [132]). Moreover, there is a suggestion that vaccination with H1N1 antigens could possibly induce cross-reactive T cells to the neuronal autoantigen hypocretin found on hypothalamic neurons, the loss of which is implicated in disease manifestation [133]. Whether or not these events could conceivably occur with other adjuvants or antigens from other influenza strains remains to be seen but nonetheless must be carefully considered in light of this possibility. Strategies to expedite pandemic vaccine distribution

For a vaccine to be efficacious during an emerging H7N9 pandemic, the outbreaks must be detected early and the Expert Rev. Vaccines 13(11), (2014)

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Considerations for the rapid deployment of vaccines against H7N9 influenza

vaccine be made available rapidly. Just as important is the deployment and utilization of comprehensive global surveillance systems and diagnostic capabilities that provide realistic coverage, particularly in regions limited in resources and access. There is an often-quoted lead time of 4–6 months from when a novel strain emerges to vaccine availability. Mathematical modeling studies have indicated that in the event of an outbreak, the implementation of social distancing measures, such as travel restrictions or closures of schools, coupled with the use of antiviral therapeutics may be sufficient to slow down transmission and hence the impact of disease in the population by reducing the strain on health care services [134]. The recommendation and manner of implementing such measures is largely guided by information provided by a network of global collaborative laboratories under the auspices and coordination of the WHO Influenza Surveillance and Response System. In conjunction with these measures, the use of existing stockpiles of vaccines during the early phase of an outbreak, even if their efficacies are reduced against the pandemic strain, must also be considered as they could have a substantial impact on reducing effects on global health and economies. In addition to existing prepandemic measures, 2006 saw the implementation of the WHO influenza vaccine technology transfer initiative aimed at establishing and developing self-sufficient vaccine-manufacturing capabilities in 11 developing countries. This incentive has been largely successful in these countries and has spurred local and regional investment and funding [135] that could ultimately lead to an increase in the local production of pandemic vaccines and facilitate the growth of essential infrastructure, allowing efficient vaccine distribution by reducing reliance on supply from first-world countries. While the emphasis remains on efforts to design, develop, test and manufacture new vaccines, we must also continue to focus our attention on the refinement of licensing processes and improvement of logistics involved in the distribution of pandemic vaccines to target populations. Present licensing procedures for seasonal influenza vaccines allow for the introduction of necessary changes to the vaccine composition following WHO recommendations. The framework of procedures governing the approval for the use of these vaccines in jurisdictions such as the USA and the EU is similar to a great extent. However, the timelines and criteria for assessing vaccine safety and immunogenicity can vary considerably and potentially lead to vaccine shortages across different jurisdictions during unexpected demand [136]. Additional challenges to licensing authorities are presented by the likelihood that a pandemic vaccine will be significantly different in antigenicity to seasonal vaccine strains, require co-administration with an adjuvant and in the case of vaccine licensure in the EU, will need to enter a clinical trial. To address these possible licensing bottlenecks and fasttrack the commencement of pandemic vaccine manufacture when needed, the EMEA as well as other international government agencies have implemented a preemptive strategy to clinically evaluate the composition and manufacturing methods of ‘mock’ pandemic-like model vaccine formulations prior to a informahealthcare.com

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pandemic being declared. In the event of an outbreak therefore only the vaccine strain will need to be updated without revisiting the entire regulatory process [137]. Guidelines and recommendations for the accelerated licensure of pandemic vaccines in the USA through supplementation of existing seasonal vaccine manufacturing licenses are in place [138] as are options for implementing fast-track approval by regulatory authorities of a pandemic vaccine [139]. While these initiatives were originally intended with H5N1 in mind, they could nonetheless also extend to vaccines against H7N9. The process of vaccine standardization, which is currently based on antibody/antigen recognition in single radial immunodiffusion assays that determine HA content, has not varied significantly since its inception and the preparation of essential reagents, for example, sheep antisera required for these assays can often take several weeks. The use of more precise and accurate reverse-phase chromatographic, mass-spectrometric and even amino acid-based techniques could potentially reduce this time frame to a matter of days [140–143]. Expert commentary

Our experiences in preparation for and our handling of past pandemic threats have consistently highlighted limitations in our ability to respond appropriately. While it is probably unrealistic to expect that these issues will be resolved quickly, there are practical options at our disposal to minimize the global effect of a H7N9 outbreak through rapid deployment of vaccines. Notwithstanding antiviral countermeasures that are presently in place, the ongoing development of novel vaccines, adjuvants, prophylactic and therapeutic approaches together with the continuing refinement of government policy and improvement of distribution hold a promise for improving our effectiveness in countering the threats posed by the everevolving influenza virus. There is no doubt that prepandemic vaccine preparedness has the potential to curb the severity of an outbreak. Once this occurs, however, and if a matched vaccine remains unavailable, we must be prepared to respond rapidly with alternative measures. The use of adjuvants that will allow protective immunity to be induced using dose-sparing amounts of vaccines, for example, will play an important role in providing coverage of the population. The existing stocks of vaccines made from phylogenetically related H7 strains should also be considered for use because they could provide some level of cross-protection. Poorly matched H7 vaccines may at least provide some B-cell memory responses, although of low affinity for the newly emerging virus, that could through hypermutation, allow production of highly specific antibodies more rapidly upon infection than through the activation of naı¨ve B cells. The increasing, and warranted, interest in eliciting crosssubtype (heterosubtypic) protection through the use of vaccine/ adjuvant combinations that induce CD8+ T cells capable of recognizing epitopes that are conserved across multiple subtypes of influenza A virus will also play an important role in strategies yet to be implemented. Certainly, the least advantage of 1331

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such an approach is that totally synthetic vaccine candidates based on this precept are simple to make [124,126,127,144–147] and in potentially huge quantities without any knowledge of amino acid sequence of the pandemic strain being necessary. Achieving and managing these objectives will undoubtedly require concerted and coordinated efforts of global communities and organizations, notably from first-world countries, to provide critical infrastructure and knowledge that will not only enable swift action in the event of a H7N9 outbreak but to also ensure the establishment of a suitable framework of responses against future pandemic threats.

existing vaccines (i.e., prime-boost regimens using LAIVs) will expand the range of options that can supplement existing countermeasures. The importance of adjuvants and vaccine delivery systems cannot be overstated. Our knowledge of the ways in which we can target the highly efficient pathogen-recognition receptors and processes inherent in our innate immune system has enabled major new approaches in vaccine delivery. Dose-sparing can be achieved and the promise of a universal influenza vaccine that induces cross-protective CD8+ T-cell responses is closer than ever.

Five-year view

Financial & competing interests disclosure

The ongoing threat posed, not only by the H7N9 virus but also by future pandemic strains, necessitates improvements and modernization of our existing vaccine manufacturing capabilities. New technologies to produce vaccines are available that will reduce and transition us beyond our reliance on traditional egg-based vaccine production. If implemented, the use of novel vaccine platforms as well as innovative ways to utilize

B Chua and DC Jackson are supported by funding from the National Health and Medical Research Council of Australia. LE Brown is an employee of The University of Melbourne. The authors have no other relevant affiliations or financial involvement 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.

Key issues • With the emergence of avian-origin H7N9 influenza virus infection in humans and its potential to cause a pandemic, efforts to contain its spread and the potential devastation it may have on global health and economies is limited by our capability to produce enough of an appropriate vaccine to protect the population. • A number of H7N9 vaccines are currently being evaluated in clinical trials as vaccine manufacturers ready themselves to commence mass production for distribution before a pandemic outbreak occurs. • Strategies that could accelerate the rate of vaccine production could result from updated vaccine quality control procedures and streamlining of licensing pathways. • The use of cell culture-produced vaccines, adjuvants, live-attenuated, recombinant and even synthetic epitope-based vaccines could be viable options to supplement and even replace traditional inactivated vaccines. • There is still a need to identify immunological correlates of protection or disease amelioration that are not subtype specific and to develop novel vaccination approaches to routinely induce these immune mechanisms so that the impact of novel influenza viruses, such as H7N9, will be greatly diminished.

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