Protecting global health security from the threat of emerging infectious diseases: are vaccine companies doing enough?

Vaccines for Emerging Infectious Diseases

Over the past 10 to 15 years, a succession of infectious diseases has emerged, with widespread effects. The West African Ebola outbreak, for example, caused more than 11,000 deaths worldwide between December 2013 and March 2016. In February 2016, as the Ebola outbreak slowed, WHO declared that birth defects related to the Zika virus amounted to a Public Health Emergency of International Concern. Within a few months, Zika had infected over one million people. Emerging infectious diseases (EIDs) can also take a toll on economies: the Ebola crisis is estimated to have had a negative impact of USD 2.8 billion in Guinea, Liberia and Sierra Leone.

Infectious diseases are considered “emerging” if they have newly appeared in a population, or are rapidly increasing in incidence or geographic range. The threat posed by EIDs differs from that posed by other diseases: local and international health systems often have little to no experience with their prevention or control.

What is more, with increased movement of people and pathogens across borders due to globalisation, threats from local infectious diseases can be quickly transformed into global problems. Urbanisation, changing patterns of contact with wild and domestic animals, and climate change further propagate vulnerability to pandemics. This means that EIDs pose a threat to the health security of all nations, regardless of where an infection first emerges. Several major outbreaks in recent years underscore this point. These include Severe Acute Respiratory Syndrome (SARS) (2003), H5N1/avian flu (2003), H1N1/swine flu (2009), Middle East Respiratory Syndrome coronavirus (MERS-CoV) (2012) and, more recently, Ebola and Zika (see figure 13).

The International Health Regulations (IHR) 2005 are a key international legal instrument designed to protect global health security in response to contemporary challenges. The IHR recognise that vaccines are crucial to preventing the spread of EIDs. Vaccine companies play an important role in this space, in coordination with national and international stakeholders. The Coalition for Epidemic Preparedness Innovations (CEPI) is a key partnership here, aiming to accelerate R&D for new EID vaccines. This analysis examines the role of vaccine companies in protecting global health security from EID threats. While animal vaccines and other measures to control zoonotic EIDs are also important, this analysis focuses on human vaccination. Data from all eight companies in the scope of the Index was examined for this analysis.

Developing and delivering vaccines for EIDS

Incentives critical to drive vaccine R&D
For many EIDs, treatments are simply not available. Where treatments are available, it can be difficult to diagnose acute infections quickly enough to facilitate effective treatment and curb the spread of infection. In this context, being able to prevent and manage EIDs by vaccinating susceptible populations adds real value. This requires the rapid development of effective vaccines. However, the response of vaccine companies to the need for R&D that specifically targets EIDs has often been limited. While vaccine R&D is generally complex and lengthy, R&D targeting EID vaccines is particularly difficult and risky for a number of reasons.

R&D targeting EIDs is most often reactive, undertaken in response to disease outbreaks. This requires flexibility, and the technologies and processes used must be consistent, highly standardised and reproducible to allow for application across diverse pathogens. In this context, traditional approaches to pharmaceutical R&D, such as random target identification, are time consuming and often fail to produce effective vaccines against EIDs.

Proactive vaccine R&D is more desirable than reactive R&D, but less common. Despite being undertaken before an outbreak occurs, proactive R&D may also require flexible and reproducible processes. This is due to the rapidly changing genetic make-up of some pathogens. Influenza is a case in point: due to its high mutation rate and frequent genetic reassortment, WHO conducts a twice-annual identification of seasonal influenza strains in each hemisphere, to which vaccine developers must respond rapidly.

The current market-driven innovation model primarily stimulates R&D that focuses on products with a predictable market and a guaranteed return on investment. This does not provide sufficient incentive for developing new vaccines for existing or predicted EID outbreaks. Investments are likely to be deemed risky, not only due to attrition rates in vaccine R&D: because the size and severity of outbreaks can be difficult to predict, companies have little certainty with regard to the market potential of newly developed vaccines. While some EIDs may never lead to major epidemics, others may become widespread. For example, vaccine developers have estimated that the annual market for a Zika vaccine could exceed USD 1 billion.

Consequently, some of the most urgently needed vaccines are not being developed.20 There are some mechanisms for incentivising vaccine R&D, such as Advance Market/Purchase Commitments (AMCs/APCs), which offer funds to guarantee the price of a currently unavailable vaccine. Donor funding can help mitigate the financial risks associated with investing in technically challenging vaccine development where return on investment is uncertain. Such funding may be delivered through product development partnerships (PDPs). PDPs have additional benefits, such as accelerating vaccine development by bringing together the diverse strengths of stakeholders. Furthermore, by facilitating access to comparator products, portfolios of R&D projects can be actively managed, and resources can be directed to those projects with higher potential impact.

The first clinical trial participant receives Johnson & Johnson’s Ebolavirus vaccine candidate. The companies in scope have two Ebolavirus vaccine candidates in phase III trials.

Post-development considerations for ensuring access to vaccines
While there is a clear need for development of novel EID vaccines, ensuring rapid, widespread access to vaccines with demonstrated safety and efficacy is equally important for preventing and controlling outbreaks. Regulatory approval processes for vaccines, which are often complex and lengthy, may be particularly challenging in the context of EIDs. Affordability is also critical to ensuring equitable access to vaccines across countries, as is the sustainability of vaccine markets: EID vaccine pricing must be carefully considered to ensure affordable access, as well as sufficient revenues to support R&D and manufacturing costs.

Furthermore, in order to ensure rapid access to sufficient supplies of vaccines if an outbreak occurs, consideration should be given to supply and deployment strategies. National, regional and global vaccine stockpiles can help support this. Global vaccine stockpiles exist for several diseases with outbreak potential, such as cholera, meningitis, yellow fever and smallpox.24 However, the 2016 yellow fever outbreak in Angola has twice depleted the global stockpile of six million doses, demonstrating that stockpiles do not guarantee sufficient supply. In such cases, the ability to rapidly scale up vaccine production is critical. Similar stockpiling mechanisms could be considered for EIDs. For example, Gavi has plans to create an Ebola vaccine stockpile. Such stockpiles will require sufficient funding, as well as strong governance and cooperation between stakeholders, including the private sector.

Current state of R&D targeting EIDS

In December 2015, WHO prioritised R&D for vaccines, diagnostics and therapeutics for those emerging diseases that are most likely to cause major epidemics, and for which few or no medical counter-measures exist (Crimean Congo haemorrhagic fever, Ebola and Marburg virus diseases, Lassa fever, MERS and SARS coronavirus diseases, Nipah and Rift Valley fever). It also designated three additional diseases as posing serious threats (chikungunya, severe fever with thrombocytopaenia syndrome, and Zika). The Access to Vaccines Index examines the vaccine R&D activities undertaken between June 2014 and May 2016 by eight major vaccine companies. Five of the emerging diseases prioritised by WHO are in scope of the Index and have no existing vaccines: chikungunya, Ebola, Lassa fever, Marburg (haemorrhagic) virus disease and SARS.

Half of the eight companies evaluated are active in this area, developing five vaccines for three of the five diseases in scope (one against chikungunya, three against Ebola and one against Ebola and Marburg; see figure 14). All five vaccines in the pipeline are being developed in partnership, suggesting that risk-sharing arrangements were important to engage the companies in these projects. The size of the pipeline for these five diseases reflects the limited incentives for major vaccine companies to engage in R&D in these areas, and for EIDs more broadly.

Case study: Companies have four Ebola vaccine candidates in the pipeline

WHO has identified an urgent need for vaccine, diagnostic and therapeutic R&D targeting the Ebola virus. The Access to Vaccines Index found that three companies evaluated had Ebola vaccine candidates in the pipeline in the period of analysis: GSK, Johnson & Johnson and Merck & Co., Inc. During the period of analysis, Pfizer discontinued its discovery stage research into Ebola. Each company’s approach to vaccine R&D targeting Ebola demonstrates the importance of coordinated and sustained incentives for driving R&D that focuses on EIDs, as well as for ensuring that companies plan ahead to make successful candidates accessible. This is especially important given traditional vaccine development often takes between 5 and 15 years.

The case of Ebola suggests that the vaccine industry is ready to respond to incentives to engage in R&D targeting EIDs. However, it also illustrates that the established system incentivises reactive over proactive R&D. All three companies accelerated Ebola vaccine development after the West African Ebola outbreak began in 2013, in response to the global prioritisation of Ebola R&D. The scale of incentives to drive Ebola vaccine R&D was significant. All three companies collaborated with multiple stakeholders and received external funding to support vaccine development. Global health stakeholders predict that an Ebola vaccine will reach the market, but the timeframe for this is unknown. When it does occur, stakeholders envision that the vaccine will be used as part of future outbreak responses. Greater global coordination is necessary to incentivise companies to engage effectively in developing and bringing to market vaccines for a full range of EID threats.

GSK

Phase II

Partnerships and funding: In August 2014, GSK formed an international consortium to fast-track the development of its Ebola vaccine candidate (ChAd3-EBO-Z). The vaccine is being developed in collaboration with partners such as the US National Institutes of Health. The partners have committed approximately GBP 25 million in R&D funding. GSK entered into negotiations with Gavi for an APC, but ultimately no agreement was reached. GSK cited concerns that the USD 5 million payment offered by Gavi did not constitute appropriate risk-sharing, as it did not sufficiently cover manufacturing costs incurred by GSK.

Access provisions: GSK has committed to continuing to develop its Ebola vaccine at its own risk and to produce the vaccine for emergency use and stockpiling purposes. The company is considering partnerships to ensure cost will not be a barrier to access in low- and middle-income countries. GSK has also committed to supplying 300,000 doses of the vaccine to Gavi for use if an epidemic re-emerges before a vaccine is approved.

Johnson & Johnson

Phase III

Partnerships and funding: In January 2015, Johnson & Johnson announced the formation of a consortium to accelerate the development of its Ebola vaccine candidate (VAC52150), which it founded together with research institutions and non-government organisations. The consortium has received EUR 102 million in Ebola R&D funding from the Innovative Medicines Initiative (a public-private partnership). The vaccine candidate is in phase II clinical trials.

Access provisions: Johnson & Johnson will take “commercially reasonable” steps to make its vaccine available in developing countries, acting either directly or through partnerships with local authorities and international organisations (e.g., WHO, UNICEF). It applied to WHO for Emergency Use Assessment and Listing (EUAL) in September 2016, a procedure for use of vaccine candidates in the context of a public health emergency.

Pre-clinical

Partnerships and funding: Johnson & Johnson has a multivalent filovirus vaccine that moved from pre-clinical into phase I clinical development since the period of analysis ended. This project is based on AdVac® technology (prime) and Modified Vaccinia Ankara Bavarian Nordic vector (boost) and aims to protect against all filovirus strains (Ebola and Marburg). It is being developed in partnership with Bavarian Nordic and received funding from the US Department of Health and Human Services.

Access provisions: Johnson & Johnson did not disclose access provisions for this project.

Merck & Co., Inc.

Phase III

Partnerships and funding: In late 2014, Merck & Co., Inc. entered into an agreement with a biopharmaceutical company, NewLink Genetics Corporation, to develop and commercialise its Ebola vaccine candidate (rVSV-ZEBOV). It is now in clinical phase III. The company is collaborating with multiple partners to continue developing this vaccine, and has received R&D funding from donors, including several US government bodies and the Wellcome Trust. Results of a major trial in Guinea, published in December 2016, showed the vaccine was highly protective against Ebola. The vaccine will be fast-tracked for regulatory approval in the EU and US.

Access provisions: In January 2016, Merck & Co., Inc. agreed to the terms of Gavi’s APC, which was declined by GSK. It has pledged to make the vaccine available to Gavi-eligible countries “at the lowest possible access price to help achieve sustainable public sector access.”36 It has also committed to supplying 300,000 doses for emergency use and/or broader clinical trials. It applied for EUAL in December 2015.

It is not clear how each company will address the affordability of its vaccine(s) in the potential absence of a viable market.

A global approach is required to respond to the threat of EIDs

The response to the Ebola outbreak prompted four global commissions to evaluate the national and global responses to the epidemic. They concluded that the approach to preventing, detecting and responding to future infectious disease threats needs to be improved. The findings of the Access to Vaccines Index support this view. The Index’s analysis of the vaccine pipelines of eight major companies for five high-priority EIDs found an insufficient level of R&D activity to ensure preparedness in preventing and controlling outbreaks of five EIDs. Ebola receives most attention, yet funding sources for Ebola vaccine development were consolidated only after the recent outbreak was underway. What is more, some of this funding has since been redirected to the current Zika outbreak. While R&D incentive mechanisms, such as AMCs/APCs, donor funding and PDPs, may effectively engage companies in R&D targeting specific diseases, such mechanisms are often employed reactively and are not well-coordinated across EIDs. A stronger framework is required to coordinate global responses so that they are focused on the most pressing EID threats.

CEPI, launched in January 2017, recognises these challenges. It brings together a range of stakeholders, including governments, industry, academia and civil society, to finance and coordinate the development of new vaccines to prevent and contain infectious disease epidemics. Donors – including the Wellcome Trust, Bill & Melinda Gates Foundation and several governments – have provided USD 460 million in initial funding for the initiative. The first disease targets will be MERS-CoV, Nipah and Lassa fever: CEPI aims to have vaccine stockpiles for these diseases by 2021. GSK, Johnson & Johnson, Merck & Co., Inc., Pfizer, Sanofi and Takeda are participating in CEPI, as well as Serum Institute of India (representing developing country manufacturers).

Similarly, GSK has proposed a dedicated, permanent Bio-Preparedness Organisation (BPO) to continuously design and develop vaccines against previously identified and newly emerging pathogens that present a threat to global health, in a “no profit/no loss” model. In late 2016, it was in discussions with interested stakeholders to assess the alignment of the BPO with global policy objectives and, if appropriate, to identify how the concept may be funded. GSK’s latest global vaccine R&D centre in the US would serve as the site for its proposed BPO. GSK has also offered CEPI the use of its R&D centre for vaccine development, at no profit to the company.

Vaccine companies should proactively engage with CEPI and other preparedness mechanisms to ensure their vaccine R&D expertise results in global benefits. Alongside enhanced R&D for EID vaccines, access provisions must be established early in the development process to ensure immunisation coverage is sufficient to protect populations in low- and middle-income countries and to prevent the spread of infections internationally. These challenges must be overcome to improve preparedness for the emergence of infectious diseases – which will inevitably occur – and ensure global health security for the future.