The WHO global influenza surveillance and response system (GISRS)—A future perspective

In the centenary year of the devastating 1918‐19 pandemic, it seems opportune to reflect on the success of the WHO Global Influenza Surveillance and Response System (GISRS) initiated 70 years ago to provide early warning of changes in influenza viruses circulating in the global population to help mitigate the consequences of such a pandemic and maintain the efficacy of seasonal influenza vaccines. Three pandemics later and in the face of pandemic threats from highly pathogenic zoonotic infections by different influenza A subtypes, it continues to represent a model platform for global collaboration and timely sharing of viruses, reagents and information to forestall and respond to public health emergencies.


| INTRODUC TI ON
In regard to sample and data sharing, we recognize the importance of the WHO global influenza surveillance and response system (GISRS) and Pandemic influenza preparedness (PIP) framework, as well as the global initiative on sharing all influenza data (GISAID).
From the Berlin Declaration of the G20 Health Ministers, May 2017. 1

| UNDER S TANDING INFLUENZ A
Initiated at a time when there was relatively little detailed knowledge about the viruses, their structure and mechanisms of infection, their ecology or the inter-relationships among the influenza viruses infecting humans and animals, research was a high priority, not only of methods for virus detection and analysis of their antigenic properties, but also of the fundamental virological properties of the virus.
Many of the advances in our understanding of influenza were made in close association with the network-the "free" sharing of viruses and information providing a vital resource for the research community. Thus, revelation of the protein composition of the virus, 4 the segmented nature of the virus genome and the structural (sequence) relationships between segments 5 in relation to genetic reassortment, and the antigenic relationships between animal and human influenza viruses, 6 as the basis of pandemics, 7,8 were closely associated with the work of members of the WHO network and the WHO CCs in particular. Elucidation of the crystal structure of the haemagglutinin (HA) provided the first clear understanding at the molecular level of antigenic drift, 9 of different receptor specificities between human and animal viruses in relation to host range restriction 10 and the mechanism of virus entry into a cell, and more generally the mechanism of membrane fusion. 11 Other notable spin-offs from research on resistance and immunity to infection were the discovery of interferon 12 and the uncovering of the peptide basis of cell-mediated immunity. 13 It is this scientific excellence within GISRS that has provided the intellectual authority and credibility for confidence, not only in the veracity of the biannual WHO recommendations on vaccine composition, but also in the procedures/methods, guidance and interpretive tools developed to anticipate the risk from seasonal antigenic/ genetic variants and emergent zoonotic infections.
Monitoring of antiviral resistance by the network 14 has also been closely aligned with more fundamental interests in the mechanisms of antiviral action and emergence of resistance. Thus, studies of resistance to amantadine revealed the target as the novel M2 proton channel. 15,16 The emergence of resistance of H1N1 and H3N2 vi-

| COMMUNI C ATI ON AND DATA S HARING
An essential aspect of the network and coordinating responsibility of the WHO GIP is the effective, rapid collation and sharing of information, via FluNet (for virological data) and FluID (for epidemiological data), including virus genetic sequence data and associated information, as well as sharing of viruses and reference reagents. on how best to promote timely sharing of genetic sequence data (GSD) pre-publication, resulted in the GISAID data sharing mechanism, the essence of which is the Database Access Agreement (DAA) 35 which governs the sharing of the data in its EpiFlu™ database. The DAA enshrines a code of conduct between providers and users of data which protects the ownership of the data while making it freely available on the proviso that users acknowledge the source of the data and, as appropriate, engage with the originators of the data in the collaborative spirit of GISRS, in a manner consistent with its original intent. 37 Its effectiveness is demonstrated by the prompt release of genetic sequences from the first cases of H7N9 zoonotic infection in China in 2013, which enabled the rapid production by synthetic biology of a candidate vaccine virus within a few weeks, 38 and in ensuring availability of the latest data for the biannual WHO vaccine consultation meetings (VCMs). 39 The close alignment of the principles underlying GISAID's sharing mechanism with the seven key principles for data sharing in a public health emergency enunciated recently by the Global Research Collaboration for Infectious Disease Preparedness (GloPID-R) 40 illustrates once again how GISRS can lead the way in implementing innovative mechanisms and procedures. GISAID, also a trust-based system, integrates GSD with other clinical, virological and epidemiological data, and takes advantage of the latest advances in rapid gene sequencing technologies. It serves as a good example of sharing GSD in relation to public health emergencies and can perhaps serve as an example for other pathogens such as of Ebola and Zika viruses. 41

| VIRUS CHAR AC TERISATI ON AND VACCINE VIRUS S ELEC TI ON
A crucial aspect of GISRS and part of its success is meeting the strict timelines for vaccine virus selection and the manufacture and quality control of vaccine, prior to distribution, a process that takes 6-8 months. 32 Thus, any developments which assist interpretation of the most up-to-date data to anticipate potential future antigenic changes are likely to be beneficial in avoiding a "mismatch" of vaccine to circulating strains, which reduces vaccine effectiveness, as That aside, it is ironic that with all the technical advance in molecular characterisation, antigenic characterisation of H3N2 viruses has become more difficult due to changes in both the specificity and affinity of receptor binding and consequent agglutination of red blood cells from different species, in addition to changes in antigenicity. 42,47 Conclusive results on antigenic relationships are no longer guaranteed from a simple haemagglutination inhibition (HI) test and antigenic characterisation relies on complementary results from neutralisation assays. 39

| PANDEMI C THRE AT FROM ZOONOTI C VIRUS E S
Much has been learned about the mechanism of HA binding to the different receptors on avian/animal and human cells for various avian subtype viruses, H5N1, H5N6, H7N9, H9N2 and H10N8, isolated from infected humans, and has indicated that affinity for both types of receptors may represent an intermediate in acquisition of human-to-human transmissibility. 50,51 However, what changes would be required and what environment would be conducive to such changes in the HA and in other virus proteins to effect efficient human-to-human transmission is simply not known. 52,53 Thus, tools for influenza pandemic risk assessment (such as IRAT from CDC 54 and TIPRA from WHO), which provide a comparative assessment of the perceived pandemic threats from zoonotic infections, in terms of severity (based on, eg the case-fatality ratio) and likelihood (based on frequency of human infection) and the characteristics of the virus being assessed, are limited in predictive capacity. While H7N9 viruses have a capacity to transmit by respiratory droplet between ferrets, 55 no increase in transmissibility between infected people has yet been detected, even during the largest outbreak in 2016-2017 and the emergence of a highly pathogenic avian influenza pathotype. 56 Nevertheless, while such a structured framework upon which to base an assessment of zoonotic viruses is imperfect, it provides a mechanism for prioritising the risks associated with specific viruses, and there can be no doubt that enhancement of collaboration between animal health and human health sectors under the One Health banner should also help to optimise the availability of useful information.
There is a clear lack of fundamental knowledge to predict the likelihood that a particular subtype could cause a pandemic. That it was another different H1N1 virus that caused the latest pandemic, 57 and not a novel subtype different from that already circulating, emphasises the adventitious nature of the emergence of a pandemic virus. That a number of different H1N1 subtype viruses have transferred to pigs points to a predilection of the H1N1 avian viruses for mammalian transmissibility. Moreover, the recent sporadic human infections by swine "variant," H1N1v and H3N2v, viruses, 58 once again begs the question as to the extent to which pandemic viruses recycle. 59 Nevertheless, the persistent circulation of the H3N2 subtype for almost 50 years attests to its resilience and ability to continue to adapt in the human population.

| SCIENTIFI C INNOVATI ON
The pandemic threat also stimulated the WHO GIP to become more On the one hand, GISRS has undergone a revolution with the introduction of molecular genetic techniques in recent years and will continue to transform its capabilities with increased introduction of NGS and multiplex molecular platforms, in high throughput or point-of care formats, for rapid highly sensitive and specific diagnosis of respiratory tract pathogens. On the other hand, the strainspecific inactivated vaccines in use have in essence changed little over the decades since their introduction more than 70 years ago.
Application of Synthetic Biology has the potential to tailor improvements in the yield of high growth/yield reassortants and remove for example undesirable substrate-selected changes from seasonal vaccine seed viruses. Given the substantial lead time and the lack of availability of vaccine ahead of the first wave of the 2009 pandemic, there is major effort to develop new "universal" vaccines and vaccination strategies to stimulate broadly reactive antibodies against conserved epitopes on surface proteins, for example M2 (M2e) 61 the HA stalk, 62 or NA, 63 or cell-mediated immunity against internal proteins, 64,65 to confer protection against a broader range of influenza A subtypes, or at least different antigenic variants within a subtype.

Introduction of new vaccines will impact the work of WHO CCs and
ERLs and require at the very least re-evaluation of the correlates of immunity and alternative vaccine potency methods.
Moreover, licensure of new antivirals, for example targeting the virus polymerase, or therapeutic monoclonal antibodies targeting, for example the HA stalk, 66,67 will require the application of new phenotypic assays to complement molecular markers for resistance. The threat of a highly pathogenic avian influenza virus causing zoonotic infections to develop into a pandemic akin to that of 1918-19 caught the imagination and galvanised a global response, one outcome of which was the PIP Framework, instituted to bolster fairness and transparency in the benefit of the "global system." It is important, however, to recognise and be aware of the potential future impact of changes to a network which has been largely autonomous and self-financed by member states for 65 years, to include more formal arrangements for receiving additional financial support from PIP partnership contributions, amounting to half of the estimated running cost of GISRS, and involving WHO, on behalf of member states, directly in formal sharing of IVPP viruses. 21 Given the success of its 70-year-old Global Influenza Programme, the WHO has a crucial responsibility for ensuring that these additional resources are used to the best advantage, in a synergistic manner, to strengthen GISRS, under the umbrella of its GIP, to enable countries to meet their IHR responsibilities and promote benefit sharing initiatives, as well as for ensuring that GISRS' extensive complementary scientific expertise and collaborative ethos remain fully engaged to the benefit of global health security.

| LOOKING AHE AD
While GISRS is at the heart of any response to influenza, improvements in vaccines, including the quest for a "universal flu vaccine," and antivirals are essential to improve the world's capability and overall effectiveness in controlling the disease. GISRS' broad vision, under the watchful eye of the WHO GIP, should continue to provide leadership in its interaction with global partners and to implement technological advances to better understand factors influencing the adaptive potential and interspecies transmissibility of the viruses and the host response to human infection. It will be essential to retain the fundamental characteristics and collaborative ethos of GISRS as it evolves under the WHO Global Influenza Programme as the front-line defence against influenza in all its forms, and as a pre-eminent example of an integrated global system for combatting infectious disease.