Are biomarkers ushering a new era in vaccine discovery?

by Ilona Baraniak

Through many decades vaccines have helped us to control a wide range of pathogens. However, vaccine development has been less successful against many complex infectious pathogens, such as e.g. HIV, Zika, CMV. In many cases a lack of scientific knowledge, unpredictable epidemiology and unfeasibility of large efficacy studies have been holding back successful vaccine development. Luckily, we see a shift of scientific and regulatory focus towards biomarkers, which might finally change this impasse.

The current landscape is insufficient to develop vaccines against several diseases

The approach to vaccine development to date has been largely empirical. While this has worked for many infectious pathogens, it has failed for many as well (Koff & Schenkelberg, 2019). These failures are usually based around complex biology, immune evasion mechanisms, pathophysiology, unpredictable epidemiology and/or combinations of those. In addition, the current state of vaccine development is an expensive, slow and laborious process, taking billions of dollars and decades of time, with less than a 10% rate of success (Pronker et al., 2013). This is of course a significant practical obstacle, making vaccine development not feasible for any small- and medium enterprises and parties other than “Big Pharma”.

For some pathogens though, it is a lack of feasibility to perform large classical efficacy studies. Vaccines are highly special pharmaceuticals, given to healthy individuals for prophylaxis – and therefore needing exceptionally safe profiles. The vaccine-specific responses must be accurately tested within the context of the overall individual biology of an individual and further biological variables, such as age and sex among other factors connected with the immune system and its responses. Also, environmental factors, such as geography and prior exposure strongly influence the immune response to vaccination. Therefore, large efficacy studies are necessary to ensure safety of the vaccine. It is precisely this step – conventional, large scale efficacy field trials – that are the bottleneck for some vaccines.

For many tropical diseases, such as Zika, Chikungunya, Malaria, Lassa Fever and many others, it is the unpredictable epidemiology that is the major obstacle for vaccines. Although the vector is present in vast geographical locations, no endemic circulation in any of the regions is present, also no surveillance programmes exist. Therefore, outbreaks are unpredictable in time, location and intensity. This practical hurdle is almost impossible to overcome, as vaccine developers cannot determine where large, expensive efficacy trials should take place. Moreover, the regulatory environment does not support ad hoc studies, impeding potential spontaneous decisions. Additional problems are usually a lack of infrastructure, remoteness and political instability. Also, military conflicts are quite common in the some endemic regions, additional impairing planning and performing of clinical studies. These challenges are well illustrated by current immunization efforts against Ebola in the Democratic Republic of Congo.

How can biomarkers solve these obstacles?

According to FDA glossary biomarker is “a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic intervention”. Long ago the field of vaccinology acknowledged the need and urgency of discovering potential biomarkers for improvement of vaccine development programmers, referring to it even as a “holy grail of vaccinology” (Plotkin, 2019). Biomarkers can overcome the “bottleneck” of classical large efficacy studies – on top of informing advanced product development, providing important data to guide public health decisions around the development of vaccines and helping with basic research, vaccine discovery, and down-selection of product candidates.

What are the regulatory challenges?

Although the need for biomarkers in vaccine development is well recognised, regulatory agencies often hesitate to give green light to programmes based on biomarkers. There are of course multiple reasons for it, most importantly: Safety concerns! As mentioned earlier, vaccines are special pharmaceuticals needing exceptionally safe profiles. This and the tremendous increase in complexity of biomarker-based vaccine development, connected with risks and uncertainties makes the regulatory pathway very lengthy and challenging. As these cases, although more common recently, are still novel and rare, no clear guidances on specific issues related to biomarkers are yet issued. This leads to the necessity of constant interactions with regulatory agencies regarding overall strategy, usefulness and validity of the biomarker, study design, public perception and concerns. As it is usually largely a matter of a debate between multiple stakeholders, different, sometimes contradicting opinion from regulatory agencies may arise.

To align vaccine development strategies with biomarkers, the FDA recently organised a 2-day biomarker workshop attended by key opinion leaders from the industry, academia, regulatory agencies and us, Biopharma Excellence. As a result of this intense and fruitful meeting, changes of current paradigms are to be expected in the future from both EMA and FDA. The undisputed need for biomarkers should pave the way to changes in the classical vaccine development, allowing alternative solutions.

We at Biopharma Excellence can help you to achieve your goals and facilitate the regulatory progress on this uncertain follow. Our team at Biopharma Excellence assisted multiple clients throughout all stages of the vaccine development process based on biomarkers and would be pleased to support you – do not hesitate to contact us for more information.

• Koff, W. C., & Schenkelberg, T. (2019). The future of vaccine development. Vaccine. doi:https://doi.org/10.1016/j.vaccine.2019.07.101

• Plotkin, S. A. (2019). Updates on immunologic correlates of vaccine-induced protection. Vaccine. doi:10.1016/j.vaccine.2019.10.046

• Pronker, E. S., Weenen, T. C., Commandeur, H., Claassen, E. H. J. H. M., & Osterhaus, A. D. M. E. (2013). Risk in Vaccine Research and Development Quantified. PLoS One, 8(3), e57755. doi:10.1371/journal.pone.0057755