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24 Jun 2024
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Tripledemic Takedown: How Human Challenge Trials are Ideal to Expedite Multivalent Vaccine Development

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Introduction

The recent rise of the "tripledemic" – the concurrent spread of the influenza virus, SARS-CoV-2 virus, and respiratory syncytial virus (RSV) – is posing significant risks, especially to older adults and those with chronic conditions or compromised immune systems.[1] Although flu and RSV have shown strong seasonal patterns, peaking in the winter months, the convergence of these viruses with COVID-19 exacerbates healthcare pressures during the winter, adding significant strain to hospital resources. The overlap in symptoms of these viruses – including fever, cough, runny or stuffy nose, and sore throat – makes it difficult for healthcare professionals to identify the specific virus from symptoms alone with distinguishing diagnostic tests required to facilitate exact diagnosis and inform treatment strategies.

The availability of Human Challenge Trials (HCT) represents a significant leap forward in our list of tools to help tackle these diseases. This blog explores how such trials can fast-track the development of multivalent vaccines, designed to protect against multiple viruses at the same time. The need for such vaccines has never been more urgent.

Moving Towards a Multivalent Vaccine

Currently, vaccines for flu, RSV and COVID-19 are formulated independently and administered separately. The tripledemic poses a unique challenge, and so a combination vaccine, which can protect against all three or even multiple viruses, is an ideal solution. Multivalent vaccines offer several benefits:

  • Increased Vaccination Uptake: Simplifying the vaccination process into a single shot can lead to higher uptake.
  • Reduced Healthcare Burden: Administering one vaccine instead of three reduces logistical challenges and the strain on healthcare systems.
  • Cost Efficiency: There is a potential for cost savings in production and administration.

Developing these vaccines through traditional methods, however, is time-consuming and complicated in terms of regulatory approval and formulation to ensure each vaccine component still remains effective and safe once combined. Regulators typically require evidence of at least safety and immunogenicity of the combined vaccine, and potentially also efficacy, even if these parameters have been established for the individual vaccines.

The Role of Human Challenge Trials

Human challenge trials (HCT), sometimes also referred to as Controlled Human Infection Studies, streamline this process by allowing simultaneous testing of multiple antigens and play a crucial role in vaccine development, especially for new technologies like mRNA vaccines. Unlike traditional field trials, which rely on participants naturally encountering a virus, HCT take a more controlled approach – experimentally inoculating the trial subjects with a specific medical grade version of the virus (the challenge virus). Separately inoculating difference participants on the trial with a different target virus ensure efficacy data is collected against all pathogen targets and facilitates efficient multivalent vaccine development.

Advantages of HCT include:

  • Precision: By deliberately exposing participants to a specific strain of the virus, there is a greater level of control – not possible in traditional field studies – and elimination of the variability seen in community-based infections. Often not all of the viruses wanting to be tested are circulating at high enough levels during the trial duration to collect sufficient data on the efficacy of all components of the combination vaccine; this issue is totally eliminated in HCT.
  • Speed of Data Generation: In traditional field trials, subjects are vaccinated and then asked to continue with their normal life, leaving it to random chance that they will be exposed to the virus of interest naturally in the community. Consequently, the majority of subjects are not exposed to the virus, so it is not possible to make any assessment of vaccine efficacy from those subjects. As all subjects in HCT are directly exposed to the virus, they all contribute to vaccine efficacy assessments and substantially less subjects are needed; these HCT are completed much faster than traditional field trials.
  • Efficiency: With statistically significant data obtained, with the help of Data Management services such as those provided by Venn Life Sciences from fewer participants than field trials, HCT are more resource-efficient and have reduced logistical and financial burdens. Furthermore, unlike field trials that often need to extend the study duration at increased cost due to one or more of the viruses of interest not circulating to high enough levels during the season the trial was run, HCT have far more predictable controlled budgets and timelines as they are not dependent on level of community circulating virus and can be conducted all year round.

HCT can also be used to complement field studies by supplying additional data for a specific pathogen in a combination vaccine that was in low circulation during the field trial, so the efficacy data is effectively supplemented by HCT data.

Whilst HCT are often run in healthy adults with no risk factors for severe illness such that they are expected to clear the infection without invention by their own immune response, HCT can also be against pathogens where an individual’s existing immunity is not expected to be sufficient to clear an infection. In such incidences, proven treatments would need to be available. Malaria is an example of this as the strain of the parasite can be carefully controlled and chosen for a HCT, to ensure that it is sensitive to antimalarial drugs and not resistant so that we can treat the subject in the HCT to prevent the development of malarial disease symptoms.

Recent Advancements

Human challenge trials are revolutionising the approach to vaccine development by offering a faster, more precise, and efficient approach to studying vaccine efficacy. As the global leader in Human Challenge Trials, in 2021, hVIVO performed the World’s first COVID-19 HCT, set up during the height of the pandemic to provide a tool to quickly test a range of different vaccines to ascertain the best one to use should the first generation of vaccines had not proven to be successful. This model has now progressed with the development of later variants of the SARS-CoV-2 virus, such as Omicron BA 5.

Another groundbreaking example is studies at hVIVO that have provided efficacy data, which had a massively positive impact in bringing RSV vaccines to market in the last few years despite there being no vaccine available since RSV was isolated in 1956. Every year in the US, the CDC estimates RSV causes 60,000 to 80,000 hospitalisations and 100–300 deaths in children under 5 years and up to 160 000 hospitalisations and 6000–10,000 deaths in adults over 65 years.[2] HCT, conducted at hVIVO, first demonstrated the efficacy of a novel RSV vaccine, which gave confidence to the market that RSV vaccination may be possible. This led to several pharmaceutical companies expediting their RSV vaccine programmes by testing their efficacy in a HCT at hVIVO and obtaining fast-track and breakthrough status with the regulators, which facilitated subsequent clinical development steps. Consequently, the quality data from the HCT gave both the vaccine producers and the regulators confidence that the vaccine can work and provide an effective solution for this unmet medical need.[3]

Conclusion

With RSV vaccines now on the market, thanks to human challenge trials conducted at hVIVO, there is greater potential to address the challenges posed by the tripledemic, by integrating such studies to significantly shorten the timeline in developing and bringing multivalent vaccines to market. While this remains a long-term objective, the development of combination vaccines, through such trials underline its ethical and practical value. Not only will this be a cornerstone to managing several respiratory viruses at the same time, but also has the potential to save thousands of lives and alleviate the burden on worldwide healthcare systems, particularly if the higher vaccine update expectations of a combination vaccine are realised.

References

  1. GSK Behind the science magazine article The ‘tripledemic’ will hit older people hard this winter - but we can reduce the impact (accessed 20 June 2024)
  2. Respiratory syncytial virus vaccines: the future is bright. Lancet Respir. Med. DOI: https://doi.org/10.1016/S2213-2600(24)00184-X
  3. Morningstar news article IN THE KNOW: hVIVO involvement in drug approval should boost interest (accessed 20 June 2024)

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