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Pichia Pastoris (Komagataella Phaffii) As a Cost-Effective Tool for Vaccine

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Pichia Pastoris (Komagataella Phaffii) As a Cost-Effective Tool for Vaccine bioengineering Review Pichia pastoris (Komagataella phaffii) as a Cost-Effective Tool for Vaccine Production for Low- and Middle-Income Countries (LMICs) Salomé de Sá Magalhães and Eli Keshavarz-Moore * Department of Biochemical Engineering, University College London, Gower Street, London WC1E 6BT, UK; [email protected] * Correspondence: [email protected] Abstract: Vaccination is of paramount importance to global health. With the advent of the more recent pandemics, the urgency to expand the range has become even more evident. However, the potential limited availability and affordability of vaccines to resource low- and middle-income countries has created a need for solutions that will ensure cost-effective vaccine production methods for these countries. Pichia pastoris (P. pastoris) (also known as Komagataella phaffii) is one of the most promising candidates for expression of heterologous proteins in vaccines development. It combines the speed and ease of highly efficient prokaryotic platforms with some key capabilities of mammalian systems, potentially reducing manufacturing costs. This review will examine the latest developments in P. pastoris from cell engineering and design to industrial production systems with focus on vaccine development and with reference to specific key case studies. Keywords: vaccines; LMICs; expression platforms; P. pastoris (Komagataella phaffii) Citation: de Sá Magalhães, S.; Keshavarz-Moore, E. Pichia pastoris (Komagataella phaffii) as a Cost-Effective 1. Introduction Tool for Vaccine Production for Low- and Middle-Income Countries (LMICs). Infectious diseases have a significant global economic and societal impact. As a result, Bioengineering 2021, 8, 119. https:// during the last two centuries, we have witnessed the remarkable success of vaccination doi.org/10.3390/bioengineering8090119 reducing the burden of infectious diseases [1]. Although vaccination continues to be the most successful and effective mechanism against infectious pathogens, a plenitude of Academic Editor: Christoph Herwig factors, such as global population growth, age distribution, traveling habits, as well as climate changes and antibiotic resistant bacteria, are causing the emergence of old and new Received: 6 February 2021 pathogens with the risk of becoming pandemic threats [2,3]. Therefore, the global demand Accepted: 24 August 2021 for vaccines is growing. Regardless of the approach that is taken, the development of an Published: 31 August 2021 effective vaccination strategy that induces long-term immunity is a common aspect and pivotal for the success of a vaccine. However, making effective vaccines against our most Publisher’s Note: MDPI stays neutral challenging diseases such as AIDS, malaria, Ebola, and dengue, has proved to be very with regard to jurisdictional claims in difficult to achieve, mainly due to the complexity of target pathogens. Recent efforts have published maps and institutional affil- been made to produce a vaccine against these, and efficacy rates of nearly 50% have been iations. reported [4]. For example, there are several vaccine candidates in clinical trials against malaria RTS/S [5], HIV (RV144, [6]), and the Ebola virus (VSV-EBOV, [7]). Despite huge impact on human health, the vaccine industry is relatively small if compared with the pharmaceutical industry. In 2017, the vaccine sector represented 3.5% Copyright: © 2021 by the authors. ($28 billion) of the worldwide prescription drug sales, and it is expected to reach $81.27 bil- Licensee MDPI, Basel, Switzerland. lion by 2027, growing at a compound annual growth rate (CAGR) of 8.7% [8]. To date, 90% This article is an open access article of the world market share is divided by only four companies: GlaxoSmithKline, Merck distributed under the terms and & Co, Sanofi-Pasteur, and Pfizer (Figure1). The vaccine industry scenario is changing, conditions of the Creative Commons not only with the growth of new markets in emerging economies, and the need for new Attribution (CC BY) license (https:// vaccines for the developing world, but also given the imperative for speed to tackle the creativecommons.org/licenses/by/ emergency situation we are living due to the COVID-19 pandemic [9]. 4.0/). Bioengineering 2021, 8, 119. https://doi.org/10.3390/bioengineering8090119 https://www.mdpi.com/journal/bioengineering Bioengineering 2021, 8, x FOR PEER REVIEW 2 of 22 Bioengineering 2021, 8, 119 vaccines for the developing world, but also given the imperative for speed to tackle2 ofthe 21 emergency situation we are living due to the COVID-19 pandemic [9]. • Other full scale companies Sanofi- e.g. AstraZeneca (MedImmune); Johnson & Pfizer Pasteur Johnson (Crucell) 22% 21% • Biotech Companies e.g. Novavax; Bavarian Nordic Others • Regional companies 10% e.g. Serum Institute of India Ltd; PT Bio Farma GSK 24% • Contract Manufactures Merck & Co 23% e.g. Boehringer Ingelheim; DSM Biologics • Product Development Partnerships e.g. International Vaccine Institute; Dengue Vaccine Initiative Sanofi-Pasteur Others Merck & Co GSK Pfizer Figure 1. Global vaccine leaders marketFigure shares. 1. Global Adapted vaccine by leaders permission market of Springer shares [8,10] Nature. Customer Service Centre GmbH: Nature [Nat. Rev. Drug Discov.][8], (Shen, A.K. and Cooke, M.T. Infectious Disease Vaccines, 2019), [copyright] [10]. Traditional vaccines are based on formulations comprising either live, attenuated or Traditional vaccines are based on formulations comprising either live, attenuated or killed, or inactivated bacteria or viruses. Although its success, there are still many issues killed, or inactivated bacteria or viruses. Although its success, there are still many issues associated with these types of formulations. Namely, their ineffectiveness in the case of associated with these types of formulations. Namely, their ineffectiveness in the case of the live attenuated ones, the possibility to lead to severe disease in immunocompromised the live attenuated ones, the possibility to lead to severe disease in immunocompromised people, and the production costs and administration makes these vaccines difficult to use people, and the production costs and administration makes these vaccines difficult to for mass immunization. Furthermore, with the increased demand of regulatory authorities, use for mass immunization. Furthermore, with the increased demand of regulatory au- such as the United States Food and Drug Administration (FDA), the European Medicines thorities, such as the United States Food and Drug Administration (FDA), the European Agency (EMA), and the World Health Organization (WHO), requiring precisely specified Medicines Agency (EMA), and the World Health Organization (WHO), requiring precisely compositions and working with whole-cell vaccines becomes particularly challenging due specified compositions and working with whole-cell vaccines becomes particularly chal- to their undefined molecules. Over the last three decades, there has been a trend towards lenging due to their undefined molecules. Over the last three decades, there has been newa trend vaccine towards formulations new vaccine that comprise formulations defined that antigenic comprise components, defined antigenic such as components, polysaccha- rides,such asnucleic polysaccharides, acids, or proteins. nucleic An acids, example or proteins. that is of An growing example importance that is of growingis that recombi- impor- nanttance proteins is that recombinantare gaining, due proteins not only are to gaining, their wide due application not only to as their biopharmaceutical wide application prod- as ucts,biopharmaceutical but also to their products, proven safety but alsorecord to their(non-infectious) proven safety and record highly (non-infectious)immunogenicity. and highlySuch immunogenicity. vaccine manufacturing processes rely on the use of recombinant proteins. AmongSuch many vaccine conventional manufacturing and emerging processes cell rely-based on the systems use of recombinant for protein proteins. production, Among ex- pressionmany conventional of recombinant and emergingprotein-based cell-based biopha systemsrmaceuticals for protein has been production, achieved expression using bac- of teria,recombinant mammalian protein-based cells, yeast, biopharmaceuticals insect cells, transgenic has plants, been achieved and transgenic using bacteria, animals, mam- and, moremalian recently, cells, yeast,cell-free insect systems. cells, The transgenic choice of plants, the most and appropriate transgenic expression animals, and, system more to gainrecently, scalability cell-free and systems. high yield, The choiceas well of as the to mostreduce appropriate cost and time, expression should systembe previously to gain identified,scalability and and normally high yield, requires as well optimizatio as to reducen at cost the and genetic time, and should cultivation be previously level which iden- istified, product-dependent. and normally requires A comparison optimization of the at ex thepression genetic systems and cultivation as well as level examples which of is recombinantproduct-dependent. protein-based A comparison biopharmaceuti of thecals expression is presented systems in the as Table well 1. as examples of recombinantIn this review, protein-based we will biopharmaceuticalsfocus on the use of yeasts is presented as recombinant in the Table protein1. expression systems,In this more review, specifically we will on focus the onapplication the use of of yeasts P. pastoris as recombinant as one
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