The case for a universal hepatitis C vaccine to achieve hepatitis C elimination

There are vast differences in the epidemiology and burden of hepatitis C across the globe that have significant implications for meeting the World Health Organization (WHO) 2030 hepatitis C elimination targets. A consequence is that responses to hepatitis C must be tailored to particular settings; major considerations include whether the epidemic is concentrated (e.g. among key populations such as people who inject drugs [PWID]) or generalised, the transmission mechanisms (e.g. syringe sharing versus iatrogenic transmission in healthcare settings), and the capacity of the health system to respond (e.g. infrastructure and human resources).

The majority of high-income countries have concentrated hepatitis C epidemics with transmission predominantly occurring among PWID [1‐3]. In settings where the prevalence of hepatitis C among PWID is less than approximately 50%, mathematical models show that treatment-as-prevention can be effective at reducing incidence as long as treatment scale-up is rapid, has sufficiently high coverage, and is supported by harm reduction to minimise re-infection and prevent epidemic rebound [4]. Many high-income countries have well-established health systems that are equipped to do this, for example Australia, Canada, and a number of European countries [5‐8]. However, if the prevalence of hepatitis C among PWID is extremely high (greater than approximately 75%, such as Fiji, Indonesia, Iran, Italy, Malaysia, Mexico, and Pakistan [9]), it is unlikely that even three monthly testing of PWID would be sufficient to achieve major reductions in incidence [4]. Settings with high prevalence among PWID are therefore likely to need significant additional prevention measures to achieve hepatitis C elimination.

Many low- and middle-income countries have generalised epidemics with disease driven by iatrogenic transmission in official and unofficial health care and through other mechanisms such as tattooing and barbershop practices, or they have mixed epidemics where there is generalised transmission in addition to transmission among PWID. The prospects of reducing hepatitis C incidence through treatment-as-prevention in these countries is low due to limited financial resources and infrastructure to support rapid testing and treatment scale-up, multiple sources of transmission, and minimal existing prevention interventions.

Vaccines for hepatitis C have been in pre-clinical development since the discovery of hepatitis C virus almost 30 years ago. Two candidates have reached phase I clinical trials, with one reaching phase II testing (see ClinicalTrials.​gov NCT01436357) [10]. While the outcome of the phase II clinical trial of a vaccine designed to generate cellular immunity (released in 2019 [11]) did not show efficacy, there remains optimism about the possibility of developing a vaccine for the prevention of hepatitis C within the next 5–10 years. However, vigorous research and development of hepatitis C vaccine candidates and the immunological requirements for natural protective immunity, as well as overall commercial interest in vaccine development, has been dampened by the discovery of direct acting antiviral therapies (DAAs), highly effective treatments for hepatitis C. The global spotlight is currently focussed on the major immediate gains being achieved through treatment. While this is justifiable in the short-term, reflecting on achievements and lessons learnt in other disease areas makes it hard to imagine a vaccine not playing a central role in long-term hepatitis C control strategies for the majority of the world.

In this study, we used a mathematical model to project hepatitis C incidence reduction following the implementation of a variety of test and treat elimination strategies in 167 countries. The strategies included different testing frequencies for PWID and the implementation of general population screening programmes. For each country, we determined which approach could achieve the WHO elimination target of an 80% reduction in hepatitis C incidence by 2030 in the most cost-effective way (as measured by cost per case averted). Where this target was not achievable, we determined the non-dominated scenario with the greatest 2030 incidence reduction. The analysis was performed with and without a theoretical prophylactic hepatitis C vaccine, to determine if additional impact and/or cost savings could be achieved if a vaccine were available, and hence the role and relative importance that a future vaccine has in achieving hepatitis C elimination.

Without a vaccine, the optimal incidence reduction strategy was to implement test and treat programmes among PWID with setting-specific testing frequencies and to undertake screening and treatment of the general population in settings with high levels of community transmission. With a vaccine available, the optimal strategy was to include vaccination within these test and treat programmes, in addition to vaccinating adolescents in settings with high levels of community transmission (Additional file 1: Appendix E—Table S8). For 69 (41%) of the countries modelled, a vaccine reduced the testing frequency required among PWID.

Of the 167 countries modelled, between 0 and 48 countries (0–29% of countries, depending on programme coverage ranging from 70 to 90%) could achieve an 80% reduction in incidence using testing and treatment alone (Additional file 1: Appendix E—Table S7). The median relative reduction in hepatitis C incidence in the optimal strategies without a vaccine was 55% (inter-quartile range [IQR] 46–70%) (Additional file 1: Appendix E—Table S7 and Fig. 3, top). With a 75% efficacious vaccine, between 15 and 113 countries (9–68%) could achieve the 80% incidence reduction target (Additional file 1: Appendix E—Table S7, Figs. 2 and 4). The median relative reduction in incidence in the optimal strategies with a vaccine available was 81% (IQR 73–86%) (Additional file 1: Appendix E—Table S7 and Fig. 3, bottom).

For countries with concentrated epidemics, the price point for a vaccine to reduce the total cost of the optimal strategy was a median US$247 (IQR US$204–442) per course (Additional file 1: Appendix E—Table S7). Below these threshold prices, the savings from less frequent testing and treatment requirements among PWID outweighed the additional cost of the vaccine. For countries with mixed epidemics, the price point for a vaccine to reduce the total cost of the optimal strategy was a median US$1.36 (IQR US$0.94–3.04) per course (Additional file 1: Appendix E—Table S7). The price point was much lower for settings with mixed epidemics because the vaccine needed to be delivered at much larger scale.

As the price per vaccination course decreased, the availability of a vaccine reduced the cost of the optimal strategy for an increasing number of countries. At US$200 per vaccination course, the optimal strategy with a vaccine was cheaper than the optimal strategy without a vaccine for 66 (40%) of the countries analysed, leading to an aggregate cost reduction of US$7.4 (US$6.6–8.2) billion across these countries compared to the optimal strategies without a vaccine available (Fig. 4). This increased to 78 (47%) of the countries analysed and an aggregate cost reduction of US$9.8 (US$8.7–10.8) billion for a US$50 per course vaccine.

For 14 countries (8%), the optimal non-vaccine strategy involved no testing and treatment programme among PWID. Common to these countries is a very high hepatitis C prevalence among PWID (> 80%). The extremely high prevalence in these settings meant that there were not many uninfected PWID, and so hepatitis C incidence was low. Scaling up treatment led to an increase in the number of susceptible PWID and a subsequent increase in incidence. Therefore, according to our modelled definition of optimal, the non-vaccination strategy with the lowest cumulative incidence in 2030 involved no intervention or cost, but also had no impact on the epidemic. This illustrates some of the challenges faced when aiming for elimination in high prevalence settings.

This study shows that vaccines can play an important role in the elimination of hepatitis C. We found that for the majority of settings, the WHO target of an 80% reduction in hepatitis C incidence by 2030 is unlikely to be achieved without additional prevention measures. Integrating a vaccine within hepatitis C testing and treatment programmes could greatly improve the feasibility and likelihood of reaching the WHO elimination incidence reduction target by directly reducing transmission and reducing the high-frequency testing burden among risk populations.

Without a vaccine or significant additional prevention measures, fewer than 29% of countries analysed were able to reduce hepatitis C incidence by 80% by 2030 in the model (Additional file 1: Appendix E—Table S7). With a vaccine available, this could increase to as many as 68% of countries, depending on programme coverage (Additional file 1: Appendix E—Table S7). More generally, when a vaccine was available the optimal incidence reduction strategy had approximately double the impact in generalised epidemic settings and approximately four times the impact in settings with a high prevalence among PWID (Additional file 1: Appendix C—Figure S11). This clearly demonstrates that while testing and treatment programmes have the potential to produce major gains towards hepatitis C elimination, they have limitations that will require additional intervention, and a hepatitis C vaccine is worth pursuing to fill this gap.

A vaccine also improved the feasibility of reaching the WHO incidence reduction target for many settings in the model, by reducing the testing burden. Consistent with previous work [4], settings with high prevalence among PWID required high-frequency testing programmes in order to reduce incidence. The optimal incidence reduction strategies for 86% of countries required six monthly testing of PWID (Additional file 1: Appendix E—Table S7). Such a high testing frequency would be burdensome to both individuals and healthcare systems meaning that for many countries this target may not be achievable through testing and treatment alone. With a vaccine available to reduce reinfection, testing requirements among PWID were reduced to either two yearly for 47 (28%) of the 167 countries or annually for 26 (16%) of the 167 countries (Additional file 1: Appendix E—Table S7), which is likely to be considerably more feasible.

For concentrated epidemic settings, which represent the majority of developed countries, a vaccine could significantly reduce the costs of hepatitis C elimination. When a vaccine was modelled at US$200 per dose, 66 countries were identified where it would reduce the cost of reaching the WHO incidence reduction target, with an aggregate cost saving of US$7.4 billion. This is because of (a) the reduced number of PWID requiring regular screening because of their vaccination status, (b) the reduced frequency of screening required, and (c) the reduced number of treatments required. Compared to achieving elimination with testing and treatment alone, the price point to save costs by including a vaccine was a median US$247 (IQR US$204–442) and US$1.36 (IQR US$0.94–3.04) per course in countries with concentrated and mixed epidemic settings, respectively. Therefore, a vaccine for hepatitis C must be cheap and simple to manufacture so that it is economically feasible to deliver at scale in low- and middle-income countries, with some costs potentially offset by profits in high-income countries. By way of comparison, the sale price of vaccines for other diseases varies greatly by pathogen and also by country [26]. For example, the Centre for Disease Control in the USA prices adult vaccines for hepatitis B at US$30.81; human papillomavirus at US$144.18; measles, mumps, and rubella at US$45.65; and varicella at US$77.57 [27]. However, in low- and middle-income countries, the hepatitis B vaccine can cost as little as US$0.16 per dose [26]. This study provides an estimation of the economic benefits of a vaccine in different settings and for a range of vaccine prices, which may be useful for vaccine developers, programme managers, and policy makers.

These results suggest that without additional prevention measures, the optimal global incidence reduction strategy for hepatitis C is to implement targeted test and treat programmes among those at high risk of hepatitis C infection and to implement hepatitis C vaccination through these programmes. It is estimated that only 20% of people with hepatitis C were diagnosed globally in 2015 [22], meaning that broad screening programmes will be required among risk populations in most settings to achieve elimination. This would provide an opportunity to achieve relatively high vaccination coverage, in particular among PWID. In addition, for settings with high rates of transmission in the general community, the model suggests that introduction of a vaccination programme for adolescents would provide additional benefit (Additional file 1: Appendix C—Table S4, generalised settings). It is therefore worth examining the potential to combine a hepatitis C vaccine with other vaccines targeting this age group such as human papillomavirus or hepatitis B.

Harm reduction for PWID has an important role to play in the hepatitis C elimination agenda. In sensitivity analyses, we tested the impact that scaling up prevention measures among PWID could have on the testing requirements, vaccination requirements, and costs of achieving the incidence reduction target. Consistent with previous modelling [7, 28], increasing prevention programmes was found to increase the impact of testing and treatment by reducing the need for retreatment (Additional file 1: Appendix D). Therefore, programmes such as needle and syringe distribution and opioid substitution therapy should be considered essential components of viral hepatitis strategies as recommended by the WHO [29].

The total cost of reaching the WHO hepatitis C elimination targets has been estimated at US$51 billion globally [30]. For many countries, the direct costs associated with hepatitis C are currently low, because there are no or limited services available to manage hepatitis C-related liver disease. As a result, the required outlay on hepatitis C testing and treatment programmes represents new costs with minimal immediate direct economic benefits. However, when the indirect economic benefits of hepatitis C elimination are considered, such as a larger and more productive workforce, this spending has been estimated to lead to a US$19 billion return on investment by 2030 [30]. The issue of cost is therefore largely one of affordability. This is relevant because in this study we have modelled the use of a vaccine alongside the scaling up of other programmes as a way to improve prevention and reduce hepatitis C transmission—only one component of hepatitis C elimination—and the vaccine was modelled to be delivered through testing and treatment programmes because they will also be required to reduce hepatitis C morbidity and mortality. Our estimate that a US$200 per course vaccine could reduce the cost of elimination by US$7.4 billion should therefore be interpreted as approximately a 15% reduction in the estimated total cost, should financing be obtained for hepatitis C elimination.

The total cost of developing a vaccine from discovery through to licensure varies widely but has been estimated at US$0.5–1.0 billion [31]. The results of the first phase II efficacy trial of a prophylactic hepatitis C vaccine designed to generate cellular immunity, released in 2019, showed no impact [11]. While much can be learned from this study, it is a reminder that a vaccine for hepatitis C will still require significant research and development investment. By comparison, billions of dollars have been invested in HIV vaccine development; in 2019, there were 39 ongoing HIV vaccine trials, with 28 past and current phase II trials [32]. For hepatitis C, the market size of a vaccine will be determined by who is to be vaccinated (target population), how often (life-long versus waning immunity with a need for revaccination) and which countries adopt a vaccination programme, with most profits derived in developed countries. However, a lack of data and a reliance on DAAs to underpin global elimination efforts is blocking interest in hepatitis C vaccine development. Like almost all vaccines, a public-private partnership is likely to be required to fund a future candidate, but to form such partnerships there must be a shift in global opinion towards one that supports the urgent development of a preventive vaccine.

The main limitations of this study relate to the hypothetical vaccine. Prophylactic vaccines for hepatitis C are currently undergoing clinical trials, and their final properties are yet to be determined. First, for our main analysis, we assumed a 75% efficacious vaccine was available with a 10-year duration of protection, which is conservative compared to what may be achievable. Second, we assumed that the vaccine had a single efficacy value (modelled as a population average across genotypes and age groups) and that the vaccine efficacy was the same in naive individuals as previously infected individuals. It remains to be determined if the immune system is fully restored after attaining DAA-mediated viral clearance and is responsive to hepatitis C vaccination. However, our sensitivity analysis suggests that vaccine efficacy post viral clearance does not change the optimal strategy and has a minor impact on cost. Third, we used a single average cost for a vaccine course that is likely to require multiple doses. Some of the costs of delivering these doses can be minimised by combining with existing interactions with healthcare providers; for example, in the scenarios being considered, the initial dose for adults is delivered with a testing interaction and so no additional staff costs would be required, and for adolescents much of the delivery costs could be avoided by inclusion with human papillomavirus or hepatitis B vaccine schedules. When a vaccine is available, it will also be important to consider the acceptability of the vaccine among all population groups and the potential for loss to follow-up between doses. The potential impact of these assumptions for our results is that (1) the average vaccine efficacy may be different than estimated (e.g. corresponding to the 50% efficacy scenarios in Fig. 4), (2) the cost of delivery may be higher than estimated (corresponding to the higher cost scenarios in Fig. 4), or (3) the achievable coverage may be reduced due to loss to follow-up between doses or people opting out of vaccination (corresponding to the lower bounds of error bars). In each of these cases, the model still projects that epidemiological and economic benefits can be gained through vaccine development.

Much of the cost-effectiveness of a future vaccine will be driven by currently unknown properties such as duration of protection, storage requirements, shelf life, number of doses required for protection, and cross-genotype efficacy. For example, if a vaccine were only effective for genotype 1, additional genotype testing may be required alongside our modelled “test (treat) and vaccinate” strategies which would greatly influence cost. If or when a vaccine does become available, follow-up studies are warranted to assess and compare the cost-effectiveness of different implementation strategies against various willingness-to-pay thresholds. Instead, the primary aim of this study was to generate evidence that a vaccine for hepatitis C has the potential to unlock health and economic benefits beyond what is achievable with DAAs alone. We modelled vaccine interventions to be scaled up between 2018 and 2023 and maintained until 2030. While this cannot happen as a vaccine is many years away, this time period is the window where DAA treatments are expected to have their greatest impact, with the model projecting that even in this period a vaccine would be a critical biomedical intervention. As more treatment uptake and epidemic data become available, new vaccine scenarios should be modelled based on the updated and more detailed epidemic curves of individual countries, in particular in the context of stabilised treatment.

These findings strongly support the case for hepatitis C vaccine development as an urgent public health need, to ensure hepatitis C elimination is achievable and at substantially reduced costs for most countries.