The world’s first dengue and malaria vaccines: what can we learn about access?

New dengue and malaria vaccines

Dengue is the fastest-growing mosquito-borne disease globally; malaria is the deadliest. The first-ever vaccines for these diseases are currently being rolled out. Sanofi received the first approval for its dengue vaccine (Dengvaxia® or CYD-TDV) in December 2015, while GSK’s malaria vaccine candidate (Mosquirix® or RTS,S) will be rolled out in pilot projects from 2018. These innovations present important opportunities for lowering the disease burden of dengue and malaria.

The Access to Vaccines Index has examined the different approaches that Sanofi and GSK have taken to developing these vaccines and to making them accessible, as well as R&D data from all eight companies in the scope of the Index. The aim is to provide insight into the challenges Sanofi and GSK face, specifically related to the characteristics of their vaccines; the dengue and malaria vaccine pipelines; and the next steps companies and other stakeholders need to take to fully and successfully implement new vaccines for these diseases in low- and middle-income countries.

New vaccines pose challenges in implementation

Dengue

Strong data-collection systems are required to maximise effectiveness
An estimated 390 million people are infected with dengue virus each year worldwide. These include 96 million cases of symptomatic dengue infection: comprising either dengue fever, which has flu-like symptoms, or the potentially fatal dengue haemorrhagic fever. The first-ever dengue virus vaccine, used alongside current preventive measures, such as vector control, could significantly strengthen prevention strategies. This could bring us closer to reaching the World Health Organization’s (WHO) goal of reducing dengue morbidity by at least 25% and mortality by at least 50% between 2012 and 2020.

Efficacy linked to prior infection
In phase III clinical trials, the efficacy of the dengue vaccine CYD-TDV against symptomatic dengue illness was found to be 65.6% for participants aged nine or older. However, individual-level outcomes varied on several factors, including the individual’s serostatus (i.e., whether they had previously been infected with dengue). In seronegative individuals, the vaccine’s efficacy was 52.5%, whereas in seropositive individuals, it was 81.1%. This may suggest that the vaccine’s efficacy is higher among those with previous dengue infection. In addition, the trials showed that vaccinating seronegative people could lead to more serious outcomes if they were infected post-vaccination.

WHO estimates that GSK’s RTS,S, used with other interventions such as bed nets, could avert up to 30% of deaths in under-fives.

Individual serological testing prior to vaccination would likely be challenging in most affected countries. Given this, WHO recommends that CYD-TDV should be implemented in areas with at least 70% seropositivity. Assuming immunisation coverage of 80%, modelling predicted a decrease in dengue incidence of up to 30% over 30 years in such areas. However, in settings with low seropositivity (defined as 10%), an increase in hospitalisation rates is expected. To maximise the positive health effects of CYD-TDV, high-quality epidemiological and surveillance data is required. This means that, where strong data collection systems do not exist, governments and other global health stakeholders may need to support activities designed to strengthen such systems.

Malaria

Vaccine requires challenging dosing schedule
Malaria places a large burden on the global population, with 214 million cases annually and nearly half a million deaths. The vaccine candidate RTS,S targets P. falciparum, one of the five species of the malaria parasite. P. falciparum is found mainly in sub-Saharan Africa, where the disease burden from malaria is also highest. In 2015, 90% of global malaria deaths occurred in this region. RTS,S could ameliorate this burden substantially. WHO estimates that up to 30% of deaths in children younger than five could be averted by RTS,S if implemented alongside current prevention and treatment interventions. Scientifically, the development of RTS,S is also significant: not only is RTS,S the first-ever vaccine against malaria, but also the first-ever vaccine to successfully target a parasite.

In a large-scale phase III trial, completed in 2014, RTS,S showed 39% efficacy against malaria after four doses in infants aged 5-17 months and 27% efficacy in infants aged 6-12 weeks. After only three doses, efficacy was lower for both groups: 28% and 18%, respectively. For the older group, the fourth “booster” dose proved critical for preventing severe malaria. Without it, there was no protection against this most serious form of the disease.

The vaccine currently needs to be administered in three doses at monthly intervals, followed by a fourth and final dose 18 months later. This is a challenging dosing schedule, with the risk that non-completion will lead to unprotected children and wasted resources. In addition, in the older age group, for whom the vaccine was more effective, the trial identified a potentially higher risk of febrile seizures, meningitis and cerebral malaria.

In 2015, RTS,S received a positive scientific opinion from the European Medicines Agency. In January 2016, WHO recommended undertaking large-scale pilot implementation programmes to test the efficacy, safety and feasibility of implementing RTS,S in real-world settings. In June 2016, Gavi, the Vaccine Alliance committed to providing up to USD 27.5 million for these pilots, on the condition that additional funding would be provided by other organisations. UNITAID provided USD 9.6 million in June, and in November 2016, The Global Fund to Fight AIDS, Tuberculosis and Malaria approved allocation of the remaining USD 15 million required for the four-year programme. The pilot is due to start in three sub-Saharan African countries (yet to be determined) in 2018.

Registration and affordability: wide differences in provisions for ensuring access

Sanofi and GSK submitted data on R&D, registration and affordability for the CYD-TDV dengue vaccine and RTS,S malaria vaccine respectively to the Access to Vaccines Index.

Dengue

CYD-TDV: developed in-house, with novel registration strategy but uncertain affordability
CYD-TDV was developed and brought to the market by Sanofi in-house, investing USD 1.6 billion over 20 years in the process. The company’s sustained interest in developing the vaccine in-house may have been due to the emergence of potentially profitable markets for a dengue vaccine, following the rapid spread of the disease, including in upper middle-income and high-income countries. This situation is in contrast with other neglected tropical diseases (NTDs), for which the potential for a commercial market is low. In this case, the lack of market incentives leads to a reliance on external mechanisms – such as product development partnerships (PDPs) – to drive vaccine R&D.

Following the approval of Sanofi’s Dengvaxia® in 2015, the Phillipines began the first public immunisation programme against dengue in 2016.

When registering CYD-TDV for use, Sanofi pursued an innovative approach. The vaccine was first registered in Latin America and Asia, where the disease burden is highest (starting in 2015 with Mexico, the Philippines and Brazil). This is different to the typical registration pathway used by major pharmaceutical companies, which prioritises registration by stringent regulatory authorities, such as those in the European Union, Japan and the US. By taking an innovative approach, Sanofi may have accelerated access to the vaccine in lower-income, dengue-endemic countries. CYD-TDV is now registered in 11 countries, including three lower middle-income countries and one low-income country.18 Sanofi has not yet applied for WHO prequalification for CYD-TDV, which is required to enable procurement by United Nations agencies such as the United Nations Children’s Fund (UNICEF).

Public immunisation programmes with CYD-TDV have begun in the Philippines and Brazil (Paraná State). Sanofi reported its pricing strategy for CYD-TDV to the Index (please refer to Research Area: Pricing & Registration). It is unclear whether this strategy will lead to affordable prices for the vaccine. Affordability is important, given that Sanofi is currently the sole global supplier of the world’s only dengue vaccine.

Malaria

RTS,S developed collaboratively, with clear access plans in place
GSK has invested 28 years in the development of RTS,S. Unlike the dengue vaccine, RTS,S was developed through a PDP between GSK and the PATH Malaria Vaccine Initiative (MVI). The development of the vaccine cost USD 656 million, including financial support received from the Bill & Melinda Gates Foundation. Collaborative models are particularly important for accelerating R&D: they can facilitate risk- and expertise-sharing in disease areas such as malaria, where commercial incentives to drive R&D are low.

As with the dengue vaccine, when RTS,S receives marketing approval, it will likely have a sole global supplier, at least initially. To mitigate any concerns this may raise, the vaccine has, from the outset, been developed following a not-for-profit model. GSK plans to submit RTS,S for WHO prequalification, and has agreed to adopt pricing that will cover manufacturing costs plus 5%. In addition, GSK has agreed to reinvest the profit margin in R&D for next-generation malaria vaccines or vaccines against NTDs. These arrangements are common in PDPs, where non-industry stakeholders are better able to influence decisions on access. GSK has reported that RTS,S will be priced around GBP 8.50 per child (based on demand of approximately 100 mn doses). It is yet to be determined if this price will prove affordable in malaria-endemic countries where the vaccine is registered.

Next-generation vaccines

There is a continuing need for vaccine R&D targeting dengue and malaria
Even though CYD-TDV and RTS,S have the potential to substantially ameliorate disease burden, R&D needs to continue, with a focus on improving these vaccines and providing alternatives. For example, for dengue, an important goal is greater efficacy in the absence of previous infection, while for malaria, efforts to improve efficacy should be balanced with a simplified dosing schedule.

Between June 2014 and May 2016, the Access to Vaccines Index evaluated the R&D activities of eight major vaccine companies with a focus on malaria and dengue. Three companies in scope of the Index in addition to Sanofi had dengue vaccine candidates in the pipeline: GSK, Serum Institute of India and Takeda (see figure 12). GSK was the only company engaged in malaria vaccine development during this time. It is not yet clear if these projects will effectively address the greatest challenges presented by the current vaccines.

GSK has a dengue vaccine in pre-clinical development. The company is working in collaboration with the Walter Reed Army Institute of Research in the US and Bio-Manguinhos/Fiocruz in Brazil. GSK is planning for local clinical trial sites and WHO prequalification, as well as affordable pricing strategies. Serum Institute of India aims to launch its dengue vaccine candidate, licensed from the US National Institutes of Health, in 2018-19. Takeda has a dengue vaccine candidate in phase III trials. It intends to seek WHO pre-qualification for its candidate and will prioritise registration in countries where clinical trials have taken place and in countries with the highest medical need. In addition to the approval of its dengue vaccine in December 2015, Sanofi is conducting post-marketing effectiveness studies and phase-III long-term follow-up studies in Latin America and Asia. These may lead to a reduced regimen and/or an expanded age-range in the indications for its dengue vaccine.

In collaboration with PATH MVI, GSK is conducting further research into delaying and reducing the size of doses (i.e., fractional dosing) for RTS,S. Results of a recent phase II challenge study, comparing alternative dosing schedules of RTS,S, show greater efficacy in healthy volunteers receiving a fractional dose schedule. A further phase II study to test this hypothesis in malaria-endemic countries is planned to begin in 2017. In December 2016, the German government announced a grant of EUR 7.8 million to PATH MVI to support this trial. If RTS,S is more effective with lower doses, this could reduce per-dose production costs and potentially improve access. The ultimate aim is to develop a second-generation vaccine that reduces malaria cases by 75%, provides immunisation for longer than two years, and targets all populations living in P. falciparum malaria-endemic regions.

RTS,S currently requires refrigeration throughout the supply chain, which is a considerable challenge in sub-Saharan Africa. GSK is therefore collaborating with the Bill & Melinda Gates Foundation to render the adjuvant contained in RTS,S thermostable for three years at temperatures of up to 30°C. This project is currently in pre-clinical stages. A thermostable vaccine could have a substantial impact on coverage in low-resource populations.

Learning from the experiences of dengue and malaria

The first vaccines for dengue and malaria represents major breakthroughs in vaccine R&D, but both vaccines present implementation challenges. CYD-TDV requires strong data collection systems and greater clarity on whether its pricing will be affordable, and RTS,S has safety concerns and a challenging dosing schedule. While the introduction of these vaccines is welcome, there is still much that needs to be done to ensure their safe and effective implementation. These efforts must not compromise the sustainability of effective vector control strategies. Continued vaccine R&D targeting dengue and malaria is also needed.

At a high level, much of the “low-hanging fruit” in vaccine development has been picked, and complex technical challenges exist in developing new vaccines. At the same time, immunisation is increasingly being recognised as an important preventive intervention, and the industry is being called on to respond accordingly. The roll-out of the new dengue and malaria vaccines suggests that the potential benefits and risk reduction offered by vaccination are increasingly being prioritised even where their efficacy is less than that of other widely used vaccines. This prioritisation reflects the heavy burden imposed by these diseases and the corresponding pressure to respond.

Where the potential benefit of immunisation is substantial, but the outcomes of vaccine candidates have so far been sub-optimal, there is a strong need for careful implementation plans that adequately test new vaccines in real-world settings. These plans must be able to respond rapidly to newly emerging data. They must also ensure new vaccines are implemented safely and cost-effectively without compromising existing interventions. The new dengue and malaria vaccines present invaluable opportunities, including for vaccine companies, to gain insights into viable models for effectively developing and implementing new vaccines that respond to contemporary global health challenges.