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The Malaria Vaccine Advisory Committee (MALVAC) is being reconvened to help WHO formulate updated guidance about public health targets and priority activities in malaria vaccine R&D. MALVAC will convene in July 2019. Briefly, recent progress in parallel to the initiation of the RTS,S/AS01 implementation pilots in Ghana, Malawi and Kenya include the evaluation of RTS,S/AS01 pre-seasonal vaccination, in seasonal transmission settings, and a study to evaluate the role of fractional doses in conditions of natural exposure. With respect to next generation candidates, R21 is a RTS,S bio-similar developed by the Jenner Institute in Oxford and the Serum Institute of India Private Limited (SIIPL). Sanaria has communicated intentions to progress their irradiated sporozoite to a phase III study starting in 2020, but it but success criteria justifying large investments investigations in vulnerable populations have not been clearly defined. Important progress in translational science is being made in development of blood stage malaria vaccine candidates, in man-to-mosquito challenge models, and in the development of monoclonal antibodies targeting malaria antigens. Progress on MALVAC activities will be reported to PDVAC regularly.
Several large-scale efficacy trials for both vaccines and broadly neutralizing antibodies (BNAbs) are ongoing. The phase III HVTN 702 vaccine trial (NCT02968849) to evaluate the ALVAC/gp120 heterologous prime boost in 5,407 healthy, HIV-negative men and women between 18 and 35 years old, is underway in South Africa with data expected in 2020. In parallel, the phase IIb HVTN 705 (NCT03060629) trial to evaluate the Ad26/gp140 heterologous prime boost in 2,637 healthy, HIV-negative women in South Africa, Malawi, Mozambique, Zambia, and Zimbabwe between the ages of 18 and 35 years is ongoing, with data expected in 2022. The Antibody Mediated Prevention (AMP) VRC01 is being evaluated under HVTN 703 (NCT02568215) & 704 (NCT02716675) with 4,625 participants enrolled across US, Brazil, Peru, Switzerland, Tanzania, Zimbabwe, Botswana, RSA, Kenya, Malawi and Mozambique, with data expected in early 2020. If these studies are successful, the next step will be to assess combinations of mAbs, and the capacity for commercial manufacturing and worldwide distribution may become a critical constraint. Encouraging regional manufacturing capability for mAbs would be helpful. The multi-component vaccines present an unprecedented level of complexity, in terms of heterologous product combinations in the same regimen and the number of doses per regimen, that will challenge health delivery systems. One leading vaccine candidate is clade C-based for use in Southern Africa, and not designed for global implementation. The licensure and policy decision pathways for global recommendation have not been clearly articulated and the level of commitment from manufacturers to commercialize these vaccine candidates will need clarification, should these efficacy studies be successful. In 2018, WHO convened global stakeholders to opine on priorities for advancing these emerging HIV interventions, the outcomes of which are articulated as ‘priority actions to prepare the pathway from clinical proof-of-concept to policy decision and use’. The report from this meeting has been submitted for publication. To summarise, to prepare for results of these studies in 2020-2022, the target product profiles and full public value proposition for both categories of products should be defined and the regulatory, policy and implementation pathways should be prepared. Economic and health benefits, cost of goods, delivery complexity, and user perspectives will constitute key considerations for roll-out of effective products. Investments in manufacturing capacity and public-sector delivery systems will be needed to prepare for product introduction and scale up. Recommendations from PDVAC: • PDVAC endorsed the need for WHO to develop consensus regarding Preferred Product Characteristics for HIV vaccines and broadly neutralizing antibodies, particularly for LMIC use, and articulation of their investment cases.
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• PDVAC proposed evaluating the relative benefits and trade-offs of the vaccine and BNAbs candidates by using a total systems effectiveness approach to ascertain information from countries on preferences and acceptability, in the context of existing interventions.
2.3 Next-generation (universal) influenza:
There are numerous influenza vaccine candidates under development that are aimed at inducing more broadly protective immunity than existing seasonal vaccines, which could increase vaccine efficacy and avoid the need for annual strain-change of the vaccine. The leading concepts for broadly cross-protective vaccines include vaccines based on hemagglutinin (HA) stem or headstem chimeras (in phase I), and HA head chimeras (preclinical) which present principally the conserved regions of the HA. Other candidates include the incorporation of conserved M2 ectodomain (phase I/II), and vaccines based on HA but with improved immunity through the addition of neuraminidase (NA) or nucleoprotein (NP), delivery by gene-expression, or alterations in dose and adjuvant formulations. The efficacy of current vaccines, and potentially of future vaccines, is subject to a number of biological challenges including immunological imprinting from infection early in life, the immunodominance of serotype-specific epitopes and of antibody lineages. One approach being developed to bypass some of the challenges seen with current candidates is mosaic antigen display in which multiple HA from different clades are presented on the same nanoparticle. Studies conducted by NIAID demonstrate that a mosaic expressing H1, H3 and two B strains elicits broad cross-reactive heterologous antibody responses that are protective in mice. This approach may provide a way to overcome antigenic diversity and immunodominance. Recommendations from PDVAC: • Given the rapid progress being made in this area, PDVAC suggested that WHO should review the current PPCs for Next-generation Influenza Vaccines that were produced in 2017 to ensure that this guidance is still appropriate and relevant. It is also recommended that PPCs be specific for the major target populations, particularly young children, pregnant women, and the elderly.
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