Nagoya Protocol Complicates Seasonal Flu Vaccine Manufacturing And Could Slow Future Pandemic Responses
Executive Summary
Industry experts contrast the multilateral response to COVID-19, which included rapid disclosure of the SARS-CoV-2 genetic sequence, with delays and complexities in accessing seasonal influenza viruses and other pathogens originating in countries that have adopted the Nagoya Protocol and implemented access and benefit-sharing legislation.
The multilateral response to the emergence of COVID-19, which included rapid sharing of SARS-CoV-2 genetic sequencing data, has heightened the focus on an international biodiversity agreement that potentially could slow the response to the next global pandemic, industry experts say.
The Nagoya Protocol is an international agreement under the Convention on Biological Diversity. It provides a framework for sharing, in a fair and equitable way, the benefits from use of genetic resources originating in a given country.
However, industry experts said that access and benefit-sharing (ABS) legislation enacted by some countries that have ratified the Nagoya Protocol increasingly is complicating efforts to access strains of seasonal influenza virus and other pathogens, such as antimicrobial-resistant bacteria.
In the case of seasonal flu vaccine manufacturing, there is growing concern about the difficulty getting virus strains due to the need to negotiate bilateral agreements with Nagoya Protocol countries in which the strains emerge. Vaccine manufacturers warn this could negatively impact timely manufacturing and availability of future flu vaccines for the northern and southern hemispheres.
Nagoya-related delays in accessing influenza vaccine virus candidate strains “is becoming an ever-increasing issue that we need to keep our finger on the pulse of,” Lauren Parker, scientific lead of live attenuated influenza vaccine strain development at AstraZeneca PLC, said in a presentation on behalf of vaccine manufacturers at a recent meeting of the US Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee.
Furthermore, experts say the Nagoya Protocol and related ABS legislation could make it difficult to respond to the next pandemic not caused by influenza, depending upon where the source pathogen first emerges.
“The timely sharing of pathogen samples and information is essential for responding to epidemics and pandemics,” Paula Barbosa, associate director for vaccine policy at the International Federation of Pharmaceutical Manufacturers & Associations, told a World Health Organization stakeholder briefing in November. “Inclusion of pathogens on the national ABS legislation is already causing delays and disruptions. Bilateral negotiation of ABS contracts is lengthy and block any possibility of quickly responding to a public health emergency.”
Barbosa said legal certainty regarding the status of pathogen sharing under ABS legislation is necessary. “We ask WHO and the broader international community to seek an effective and internationally coherent approach mindful of national global health and economic security concerns to address the need to keep sharing of pathogens and associated information faster and predictable.”
Original Intent Misaligned With Public Health Response
The Nagoya Protocol was adopted in October 2010 and entered into force in October 2014. (Also see "Biodiversity Protocol Requires Countries To Track Patents On Genetic Resources" - Pink Sheet, 15 Nov, 2010.) It was intended to create greater legal certainty and transparency for both providers and users of genetic resources by establishing more predictable conditions for access to genetic resources, and helping to ensure benefit-sharing when those resources leave a country.
Sharing of genetic resources for research and development or commercial applications is subject to prior informed consent and mutually agreed terms between the country providing the resource and the acquirer, be they a public or private sector entity or an academic researcher. Benefits provided to the country may be monetary in nature, such as royalties on commercial products derived from the genetic resource, or non-monetary, such as the sharing of research results.
As of 17 March, 129 countries or regional entities, including the EU, are parties to the Nagoya Protocol. Among the countries that are not parties are the US, United Kingdom and Australia.
“Do we want to preserve the biodiversity of pathogens? Not really.” – IFPMA’s Paula Barbosa
Human pathogens, including influenza, are considered to fall under Nagoya’s scope. However, the sharing of influenza pathogens of pandemic potential is carved out because this is covered under the WHO’s Pandemic Influenza Preparedness (PIP) framework.
National ABS legislation varies by country, and it is not always clear whether such rules cover human pathogens, experts said.
Industry sources said the original intent behind the Convention on Biological Diversity (CBD) and Nagoya are not aligned with the need to quickly share pathogens to address an emerging public health issue.
A biopharma industry source told the Pink Sheet that the CBD was established with the idea that if researchers access a botanical that ultimately is used to develop a cosmetic, for example, the country that was the source of that botanical would derive some benefit.
“It is a completely different lens of accessing a virus or a bacteria that took hold in a certain region of the world or country, and then you’re entering into an access and benefit-sharing agreement on accessing that virus in order to make a product to kill that,” the industry source said. “The script is a little bit flipped on what [were] the original guiding principles of the CBD.”
“Do we want to preserve the biodiversity of pathogens? Not really,” IFPMA’s Barbosa said in an interview with the Pink Sheet.
‘Nervousness’ Around Seasonal Flu Vaccines
Acquisition of human pathogens from Nagoya parties with national ABS legislation can involve months or years of bilateral negotiations over the sharing of benefits and access. This, in turn, creates a situation not well suited for the frequent reformulation of seasonal influenza vaccines or for quickly responding to a public health crisis.
“We do need to take the time to formalize any legal benefit-sharing arrangement that may fall under the Nagoya Protocol,” AstraZeneca’s Parker told the VRBPAC meeting, during which the panel made vaccine strain selection recommendations for the 2021-2022 influenza season. (Also see "Dearth Of Seasonal Flu Adds Uncertainty To Vaccine Strain Selection For Next Season" - Pink Sheet, 8 Mar, 2021.)
“This can take a range of time depending on how complex the legislation is and what’s expected of the manufacturers by the country. It can take months to actually get everything necessary in place.”
The viral strains included in seasonal flu vaccines often change during the course of a single year because separate vaccine formulations are developed for the northern and southern hemisphere flu seasons. Those formulation decisions, which are made by entities such as the WHO and the FDA months in advance of the flu season, are guided by the predominant strains circulating at the time.
“Every six months we need to be prepared that WHO might recommend something that comes from a Nagoya country,” Barbosa said. “This is a problem for influenza.”
In some cases, seasonal flu vaccine manufacturers have not be able to readily access potential vaccine candidate strains that originated in Nagoya Protocol countries and, instead, have looked to neighboring countries where similar strains emerged but access is easier.
“For diseases where you have time to plan strategically as a company, companies can indeed do their research and if they … need something from a country that has Nagoya legislation in place they can work that out,” another industry source told the Pink Sheet. However, “there’s some nervousness around seasonal flu and the uniqueness of how it is, how the strains are determined, how the vaccine is developed,” and the timelines involved.
A February 2020 WHO report on the PIP framework for sharing of pandemic influenza viruses included a host of suggestions for mitigating hurdles to sharing of seasonal influenza viruses. Among these were that the WHO Secretariat encourage countries that have not yet implemented national ABS and Nagoya Protocol legislation to give special consideration to processes that facilitate rapid sharing of influenza viruses and other pathogens, and ideally exclude seasonal influenza viruses from ABS requirements.
Nagoya Not A Factor In COVID Response
Although the Nagoya Protocol has not really factored into the world’s response to the COVID-19 epidemic, it potentially could limit the ability of public health officials, researchers and industry to quickly respond to a future pandemic not caused by influenza, experts said.
China, where the SARS-CoV-2 virus originated, is not a party to Nagoya.
Following detection of the virus, the decision quickly was made to leverage the WHO’s Global Influenza Surveillance and Response System (GISRS) and GISAID (originally known as the Global Initiative on Sharing All Influenza Data) for sharing of SARS-CoV-2 virus samples and genetic sequence data. Genetic sequence data also were uploaded to other databases.
“Large-scale, rapid, geographically dispersed sharing of SARS-CoV-2 sequences has generally occurred during the pandemic, with depositions into GISAID being made from laboratories in over 100 Member States,” the WHO said in a January 2021 report on the public health implications of the Nagoya Protocol’s implementation.
In addition, the WHO established a COVID-19 reference laboratory network, in which participating labs agreed to support laboratory capacity building in low- and middle-income countries for COVID-19 diagnosis, provide a global reference source of well-characterized viral strains and sequences, and track evolution of the virus.
The early and easy access to the SARS-CoV-2 genetic sequence created a level playing field for COVID-19 vaccine development, which is why companies all over the world have been able to develop different vaccines at the same time, Barbosa said.
WHO Director-General Tedros Ghebreyesus cited the need for a globally agreed system for sharing pathogen materials and clinical samples that is not based on bilateral agreements and does not take years to negotiate.
“We haven’t actually had a Nagoya discussion around COVID,” an industry source said. However, it might have been a different story had SARS-CoV-2 originated in a country that is a party to the Nagoya Protocol. “It’s about where it starts and whether they’re in Nagoya and whether they have legislation that says all these things are mine or not, and you have to come to me.”
In addition, the rapid exchange of genetic sequencing information for a virus or other human pathogens might not be so simple in the future. “The next big conversation that will happen within Nagoya is how should one treat all the digital scientific information surrounding a pathogen,” the industry rep said.
The collaborative efforts to quickly share information related to the SARs-CoV-2 virus could serve as a model for future pandemic responses.
“If we can, over the next few months, really claim success with the multilateral response, maybe we veer towards that idea, rather than having a whole other set of rules around pandemic pathogens that slow things down,” the industry rep said.
In his closing remarks at the World Health Assembly meeting in November, WHO Director-General Tedros Ghebreyesus suggested a potential new framework for pandemic pathogen sharing.
The COVID-19 pandemic has highlighted the urgent need for a globally agreed system for sharing pathogen materials and clinical samples to facilitate the rapid development of medical countermeasures, he said. “It can’t be based on bilateral agreements, and it can’t take years to negotiate.”
“We are proposing a new approach that would include a repository for materials housed by WHO in a secure Swiss facility; an agreement that sharing materials into this repository is voluntary; that WHO can facilitate the transfer and use of the materials; and a set of criteria under which WHO would distribute them,” the director-general said.