Why do we not have vaccines for HIV and hepatitis C? An overview of current challenges

Vaccines play a crucial part in modern-day healthcare and immunisation represents one of the most effective public health interventions¹. The measles, mumps and rubella (MMR) vaccine is over 95% effective in preventing clinically confirmed measles in children². The shingles vaccine is over 91% effective in preventing herpes zoster in elderly adults³. The hepatitis B vaccine has been administered over 1 billion times worldwide and has reduced the prevalence of chronic infection in children from 4.7% to less than 1%⁴. Numerous clinical studies have demonstrated these vaccines, and others, are well tolerated and adverse events following immunisation are generally mild and transient^1–4.

Unfortunately, many pathogens without available vaccines remain and these continue to impact human health and quality of life⁵. Two key examples of this are the human immunodeficiency virus (HIV) and hepatitis C virus (HCV)^6,7. The antiviral treatments developed for HIV and HCV have certainly revolutionised care for these conditions^6,8. However, many experts agree that until we have a vaccine, it is likely that these pathogens will continue to pose a significant global health issue⁶.

Therefore, the question stands: why, after many years of HIV and HCV impacting millions of lives, do we still not have a vaccine?

Unfortunately, there are multiple reasons for this.

Genetic instability and variability

One of the main scientific hurdles to vaccine development can be the genetic instability and variability of the target pathogen. This is the case for HIV, which has a high rate of mutation and recombination that occurs during viral replication⁹. This is attributed to its error-prone reverse transcriptase, causing approximately 1 to 10 mutations per genome per replication cycle⁹. An unstable genetic structure contributes to the issue of a large global diversity of circulating strains. For HIV, circulating strains differ from one another by approximately 20% in relatively conserved proteins and up to 35% in the envelope⁶. This results in an unimaginable variety of the single viral envelope glycoprotein, Env, which is the main antigen and an obvious key target of a vaccine^9,10.

Similarly, HCV has high mutation rates driven by its error-prone RNA polymerase⁷. There are 8 HCV genotypes, which have a 30% variation in the nucleotide sequence, and around 90 confirmed subtypes, which exhibit a 15% variation in nucleotide sequence^7,11. Difficulty lies in creating a vaccine that would elicit an immune response with enough breadth to protect against all strains of the virus⁵.

Immune system evasion

Our most effective vaccines trigger an immune response that mimics the natural biological response to infection with the pathogen⁵. However, HIV and HCV are excellent at evading the immune system and cause a less-than-optimal host immune response^5,7. One way these viruses evade immune attack is by masking their epitopes, the antigenic determinants that are recognised by the host immune system^6,7. Glycosylation of envelope proteins results in a shield that hides the epitopes and diminishes the binding of neutralising antibodies^6,7. It has also been reported that HCV employs ‘decoy’ epitopes on secreted extracellular vesicles that direct the immune system away from the epitopes on the viral surface¹². Therefore, vaccines for HIV and HCV cannot be created based on mimicking the host immune response and research is required to investigate alternative strategies^5,7.

Unclear correlates of protection

Many vaccines have been developed by examining the immune response of individuals who have recovered from, or show a reduced susceptibility to, the infection¹⁰. We can then identify the immune effectors that are correlates of protection (CoP), which can be the target of preclinical research, and used to measure vaccine efficacy in clinical research¹³. The CoP for diseases with available vaccines (such as the MMR, shingles and polio vaccines) include either binding antibody responses, functional antibody responses, or cellular immunity¹³.

Unfortunately, in the case of HIV, no known human has naturally recovered from infection, so it is not clear which immune effectors are the CoP^5,13. This is due, in part, to the fact that HIV infects and destroys CD4⁺ T cells, which affects both the antibody response and cellular immunity⁵.

Lack of an animal model

The scientific hurdles described so far dictate the need for further preclinical and clinical research. However, research for HIV and HCV have been hindered by the fact that there are no appropriate small animal models for these infections^7,10. Ethical considerations and the fact that many clinical trial candidates receive antiviral therapies add another level of complexity to clinical research⁶. For example, a live attenuated HIV vaccine cannot be trialled due to the risk of reversion to the wild type⁶.

Where do we go from here?

Developing vaccines for HIV and HCV are not easy tasks. HCV is highly complex and HIV is unlike other viruses^6,7. However, despite the numerous scientific challenges, progress is being made⁹. For example, to counter the high strain variability, polyvalent vaccines are being investigated for both HIV and HCV^14,15. Like the approach used for the development of COVID-19 vaccines, the field is now trying the accelerate vaccine development for HIV and HCV by rapidly advancing promising candidates to adaptive clinical trials^7,9. Ongoing research efforts combined with insights from the recent pandemic suggest that whilst it is, and will be, challenging to develop vaccines for HIV and HCV, it is possible.

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