Role of Biomarkers in Vaccine Development

Most traditional vaccines are based on inactivated or attenuated pathogens or on purified pathogen subunits, such as toxins or polysaccharides. These vaccines are quite efficient in preventing infections of pathogens with a low degree of antigen variability because they work by eliciting functional antibodies that can (i) counteract viral invasion, (ii) neutralize bacterial toxins and (iii) induce complement- mediated killing of bacteria (Germain 2010). Vaccines containing multiple antigens (multivalent) have also been produced to cope with the viruses and bacteria that are capable of more moderate degrees of antigen variability (Pomfret et al. 2011). Strategies that have been employed to manage bacterial and viral diversity are based on new technologies that can be applied to the vaccines to prevent infection by highly variable pathogens. These include the use of reverse vaccinology, and analytical and structural vaccinology to cope with either bacterial or viral diversity.

Company

Approaches

Examples

Novartis

Multiple approaches, i.e. more than one type of bionrarker (DNA, RNA, protein, biochemical) is considered be essential to detection.

Novartis has early bionrarker plans in place for nearly each compound.

Novartis evaluated genotypes and identified 12 SNPs in six genes that permitted researchers to stratify patients in a CNS clinical trial to maximize the difference in response after 4 and 12 weeks of treatment.

Eli Lilly & Co

Many different markers are pursued simultaneously, including DNA. RNA. protein, and metabolites; the goal is to think in terms of systems biology when deciphering the data.

80-90% of clinical trials phases I- II have some form of bionrarker measurement to support the elucidation of drug activity, safety, and efficacy parameters.

Novel bionrarkers. not previously associated with sepsis, were used in clinical trials of Xigris (drotrecogin), a new drug for sepsis.

Bristol-Myers

Squibb

A mix of technologies chosen to create a panel depends on the biological endpoint being investigated, particularly biologically heterogeneous endpoints. Bionrarkers are used in phase II and III trials of competitive compounds in the same class. Class-specific rather than drug-specific bionrarkers are considered to be more cost effective at the physician/patient level, which is an important consideration in promoting the widespread use of personalized treatment.

Ixabepilone (BMS 247550) and Taxol (paclitaxel) both affect polymerization of tubulin, preventing cellular division. To see if they share some markers for drug response, tests were done in human cell lines and animals and showed that gene changes from IC50 response in a human cell fine predictive model had similarities with a response profile in animals. By the time the compound progressed to an early phase II trial, the markers that had been identified were used in human patients to predict drug response of the tumor.

Bayer AG

Bionrarkers are included in nearly drug discovery and development all programs at some level.

Since oncology is a top priority, nearly all clinical trials in this area include bionrarkers

Pfizer

80-90% of clinical trials phases I- II have some fomr of bionrarker measurement. The exceptions are situations when efficacy trials are simple and inexpensive to conduct, or when traditional tests are so good that bionrarkers are not expected to substantially improve decision making.

Roche

The search for predictive bionrarkers should begin during preclinical research. Ideally, predictive marker candidates should have been identified by the time early clinical development starts.

Predictive markers can help to focus clinical development and lead to more efficient drug development. Co-development of diagnostic test is critical.

Merck & Co

Merck is using an advanced, integrated bionrarker approach to R&D to help eliminate failures sooner and bring innovative products to patients faster. Using an integrative genomics approach to elucidate complex traits like disease and drug response. Merck scientists have identified and validated several novel drug targets and bionrarkers.

Merck uses phosphoproteonrics to identify potential bionrarkers for predicting the efficacy of drugs targeting a cancer-linked signaling pathway.

© Jain PharnraBiotech

Novel adjuvants, delivery systems, new viral vectors and prime-boost strategies can be used to elicit multifunctional adaptive responses during the vaccination protocol. Systems vaccinology approach is used to better understand correlates of vaccine efficacy and evaluate quality of humoral and cellular responses to vaccination (Michan et al. 2012). Biomarkers of immune response will play an important role in vaccines of future.

A major challenge for vaccinology is that there is no way to measure germinal center activity, particularly in human clinical trials of candidate vaccines (and most nonhuman primate studies of candidate vaccines), because germinal centers (GCs) are the engines of antibody (AB) affinity maturation, which is the goal of all AB-eliciting vaccines. For example, significantly higher levels of plasma CXCL13 (chemokine C-X-C motif ligand 13) are associated with the generation of broadly neutralizing ABs (bnABs) against HIV in HIV-infected individuals. GCs optimize B cell AB responses and are required for almost all B cell receptor affinity maturation; thus providing a critical parameter to monitor if HIV bnABs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4+ T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 (chemokine C-X-C motif receptor 5) chemokine axis plays a central role in organizing both B cell follicles and GCs and is a biomarker of germinal center activity (Havenar-Daughton et al. 2016). The authors show explicit relationships between plasma CXCL13 concentrations and germinal center frequencies in lymph nodes in a series of different conditions, including licensed and experimental vaccines, and in humans, nonhuman primates, and mice. These findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.

 
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