Hepatitis C virus causes both chronic and acute infections and a total of two million new cases per year make it a global problem. In this context, the WHO has set a target to reduce new cases by 80% until 2030. However, even the advanced countries are struggling in this fight and they don’t look like they can reach the target, with a few exceptions. A vaccine would have a huge impact towards achieving that goal.
Vaccine development for HCV appears to have a number of reasons for the unsuccessful, so far, attempts for an effective result. Those challenges are:
- The large diversity of HCV, which is driven by a high mutation rate, together with virus high production levels and subsequently a high natural selection pressure. Thus, the eight genotypes that have been characterised so far, each has a nucleotide sequence that varies by 30% vs. the others
- HCV is highly elusive to the host’s immune response, thus its ability to cause chronic infections. This ability is due to:
- Immunodominant epitopes triggering the immune system to produce antibodies that are non-neutralising, since these same epitopes act as shields
- Formation of a glycan shield through envelope protein glycosylation
- Non-synonymous mutations shifting of the glycosylation site, making it harder to target
- Factors originating from the host, such as high-density lipoprotein (HDL; increased infectivity), high apoE (masking E2 epitope), E2-coated lipid droplets (act as decoys) and resistance to antiviral interferon-induced transmembrane proteins
- A lack of in vitro models that has always been hindering the effort, as there was no way to assess different antibodies’ effectiveness. However, in the recent years, we were able to develop models and this obstacle seems to be ready to be surpassed
- A lack of in vivo models is another obstacle since humans are the natural host for HCV, it is clear that another suitable host must be found for testing. The closest relative and the best substitute would be the chimpanzees, but ethical issues prevent us from using them. A chimeric or transgenic mouse, capable of producing humanised liver cells, is the next best thing and a recent development. However, even this solution comes with set-backs, like the lack of exhibiting cirrhosis or hepatocellular (HCC)
- Rational design of an immunogen could strive to present epitopes to suitable antibody conformations, but this has not been investigated to a great length, yet. This is due to technical challenges presented by the rational design of HCV epitopes
- Virulence factors of HCV are yet to be determined, thus making a vaccine based on live attenuated or whole inactivated virus (like in other pathogens) impossible at the moment
- Targeting people who inject drugs (the major source for HCV infection) leaves a very narrow window to intervene with a vaccine. This is an argument for those asking for a universal vaccination program
- Of course, despite the scientific obstacles, there are financial/commercial obstacles too. A pharmaceutical company investing in the development or acquirement of a successful vaccine can expect limited return if the vaccination is restricted to high-risk groups in developed countries (due to vaccine price or other scientific factors)
The list goes on, as there are several more factors relating to scientific obstacles, vaccine development strategies, selecting target groups (who and when), etc. However all these setbacks should not hinder us from pursuing a working vaccine, especially when so much progress has been achieved. Moreover, there are more serious reasons to keep trying and they are summarised below:
- A globally high number of chronic HCV patients which is increasing
- A high treatment cost, which makes any viable vaccine solution preferable
- Screening of chronic carriers (90% remain asymptomatic for years) in order to receive antiviral therapy is a major logistic and economic problem
- Models for the progression of the epidemic suggest that the WHO target will not be met, unless efforts for a vaccine are intensified
- Curing a patient doesn’t mean that immunity has been achieved. Re-infection is possible
- The only human infectious diseases ever eradicated are smallpox (1980) and polio (we are very close to that target) and it is due to vaccines
- Even partial efficacy from a prophylactic vaccine would be preferable to none and this is now believed to be feasible
#hcv #vaccines #infectiousdiseases
Sources
http://perspectivesinmedicine.cshlp.org/content/10/2/a036947.short
https://www.mdpi.com/2076-393X/8/1/90/htm
https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31182