Although new facility construction or repurposing/ re-qualification may not immediately help with the current pandemic, given that only existing and qualified facilities will be used in the near term, it will position the industry for the rapid scale-up of countermeasures that may be applied over the next several years. An example is the April 2020 announcement by the Bill & Melinda Gates Foundation of its intention to fund “at-risk” development of vaccine manufacturing facilities to accommodate pandemic-relevant volumes of vaccines, before knowing which vaccines will succeed in clinical trials. Manufacturing at-risk with existing facilities is also being implemented on a global scale. The Serum Institute of India, the world’s largest vaccine manufacturer, is producing at-risk hundreds of millions of doses of the Oxford University COVID-19 vaccine, while the product is still undergoing clinical studies.12 Operation Warp Speed 13 in the United States is also an at-risk multi-agency program that aims to expand resources to deliver 300 million doses of safe and effective but “yet-to be-identified” vaccines for COVID-19 by January 2021, as part of a broader strategy to accelerate the development, manufacturing,pot with drainage holes and distribution of COVID-19 countermeasures, including vaccines, therapeutics, and diagnostics. The program had access to US$10 billion initially and can be readily expanded. As of August 2020, OWS had invested more than US$8 billion in various companies to accelerate manufacturing, clinical evaluation, and enhanced distribution channels for critical products.
For example, over a period of approximately 6 months, OWS helped to accelerate development, clinical evaluation , and at-risk manufacturing of two mRNA based COVID-19 vaccines, with at least three more vaccines heading into advanced clinical development and large-scale manufacturing by September/October 2020.At the time of writing, no PMP companies had received support from OWS. However, in March 2020, Medicago received CAD$7 million from the Government of Quebec and part of the Government of Canada CAD$192 million investment in expansion programs , both of which were applied to PMP vaccine and antibody programs within the company.15Once manufactured, PMP products must pass quality criteria meeting a defined specification before they reach the clinic. These criteria apply to properties such as identity, uniformity, batch-to-batch consistency, potency, purity, stability , residual DNA, absence of vector, low levels of plant metabolites such as pyridine alkaloids, and other criteria as specified in guidance documents . Host and process-related impurities in PMPs, such as residual HCP, residual vector, pyridine alkaloids from solanaceous hosts , phenolics, heavy metals , and other impurities that could introduce a health risk to consumers, have been successfully managed by upstream process controls and/or state-of-the-art purification methods and have not impeded the development of PMP products . The theoretical risk posed by non-mammalian glycans, once seen as the Achilles heel of PMPs, has not materialized in practice. Plant-derived vaccine antigens carrying plant-type glycans have not induced adverse events in clinical studies, where immune responses were directed primarily to the polypeptide portion of glycoproteins . One solution for products intended for systemic administration, where glycan differences could introduce a pharmacokinetic and/or safety risk , is the engineering of plant hosts to express glycoproteins with mammalian-compatible glycan structures .
For example, ZMapp was manufactured using the transgenic N. benthamiana line ΔXT/FT, expressing RNA interference constructs to knock down the expression of the enzymes XylT and FucT responsible for plant-specific glycans, as a chassis for transient expression of the mAbs . In addition to meeting molecular identity and physicochemical quality attributes, PMP products must also be safe for use at the doses intended and efficacious in model systems in vitro, in vivo, and ex vivo, following the guidance documents listed above. Once proven efficacious and safe in clinical studies, successful biologic candidates can be approved via a BLA in the United States and a new marketing authorization in the EU.In emergency situations, diagnostic reagents, vaccine antigens, and prophylactic and therapeutic proteins may be deployed prior to normal marketing authorization via fast-track procedures such as the FDA’s emergency use authorization .16 This applies to products approved for marketing in other indications that may be effective in a new emergency indication , and new products that may have preclinical data but little or no clinical safety and efficacy data. Such pathways enable controlled emergency administration of a novel product to patients simultaneously with traditional regulatory procedures required for subsequent marketing approval. In the United States, the FDA has granted EUAs for several diagnostic devices, personal protective devices, and certain other medical devices, and continuously monitors EUAs for drugs. For example, the EUA for chloroquine and hydroxychloroquine to treat COVID-19 patients was short-lived, whereas remdesivir remains under EUA evaluation for severe COVID-19 cases. The mRNA-based SARS-CoV-2 vaccines currently undergoing Phase III clinical evaluation by Pfizer/BioNTech and Moderna/ NIAID, and other vaccines reaching advanced stages of development, are prime candidates for rapid deployment via the EUA process. No PMPs have yet been granted EUA, but plant-made antibodies and other prophylactic and therapeutic APIs may be evaluated and deployed via this route. One example of such a PMP candidate is griffithsin, a broad-spectrum antiviral lectin that could be administered as a prophylactic and/or therapeutic for viral infections, as discussed later.
The FDA’s EUA is a temporary authorization subject to constant review and can be rescinded or extended at any time based on empirical results and the overall emergency environment. Similarly, the EU has granted conditional marketing authorisation to rapidly deploy drugs such as remdesivir for COVID-19 in parallel with the standard marketing approval process for the new indication.The regulations commonly known as the animal rule 17 allow for the approval of drugs and licensure of biologic products when human efficacy studies are not ethical and field trials to study the effectiveness of drugs or biologic products are not feasible. The animal rule is intended for drugs and biologics developed to reduce or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances. Under the animal rule, efficacy is established based on adequate and well-controlled studies in animal models of the human disease or condition of interest,large pot with drainage and safety is evaluated under the pre-existing requirements for drugs and biologic products.As an example, the plant-derived mAb cocktail ZMapp for Ebola virus disease, manufactured by Kentucky Bioprocessing for Mapp Biopharmaceutical 18 and other partners, and deployed during the Ebola outbreak in West Africa in 2014, was evaluated only in primates infected with the Congolese variant of the virus , with no randomized controlled clinical trial before administration to infected patients under a compassionate use protocol . Although the fast-track and streamlined review and authorization procedures described above can reduce time-to-deployment and time-to-approval for new or repurposed products, current clinical studies to demonstrate safety and efficacy generally follow traditional sequential designs. Products are licensed or approved for marketing based on statistically significant performance differences compared to controls, including placebo or standards of care, typically generated in large Phase III pivotal trials. One controversial proposal, described in a draft WHO report , is to accelerate the assessment of safety and efficacy for emergency vaccines by administering the medical intervention with deliberate exposure of subjects to the threat agent in a challenge study.
Although the focus of the WHO draft report was on vaccines, the concept could conceivably be extended to non-vaccine prophylactics and therapeutics. Results could be generated quickly as the proportion of treated and control subjects would be known, as would the times of infection and challenge. Challenge studies in humans, also known as controlled human infection models or controlled human infection studies , are fraught with ethical challenges but have already been used to assess vaccines for cholera, malaria, and typhoid . The dilemma for a pathogen like SARS-CoV-2 is that there is no rescue medication yet available for those who might contract the disease during the challenge, as there was for the other diseases, putting either study participants or emergency staff at risk .In the EU, the current regulatory environment is a substantial barrier to the rapid expansion of PMP resources to accelerate the approval and deployment of products and reagents at relevant scales in emergency situations. A recent survey of the opinions of key stakeholders in two EU Horizon 2020 programs , discussing the barriers and facilitators of PMPs and new plant breeding techniques in Europe, indicated that the current regulatory environment was seen as one of the main barriers to the further development and scale-up of PMP programs . In contrast, regulations have not presented a major barrier to PMP development in the United States or Canada, other than the lengthy timescales required for regulatory review and product approval in normal times. Realizing current national and global needs, regulatory agencies in the United States, Canada, the EU, and the United Kingdom have drastically reduced the timelines for product review, conditional approval, and deployment. In turn, the multiple unmet needs for rapidly available medical interventions have created opportunities for PMP companies to address such needs with gene expression tools and manufacturing resources that they already possess. This has enabled the ultra-rapid translation of product concepts to clinical development in record times – weeks to months instead of months to years – in keeping with other high-performance bio-manufacturing platforms. The current pandemic situation, plus the tangible possibility of global recurrences of similar threats, may provide an impetus for new investments in PMPs for the development and deployment of products that are urgently needed.An effective vaccine is the best long-term solution to COVID-19 and other pandemics. Worldwide, governments are trying to expedite the process of vaccine development by investing in research, testing, production, and distribution programs, and streamlining regulatory requirements to facilitate product approval and deployment and are doing so with highly aggressive timelines . A key question that has societal implications beyond vaccine development is whether the antibody response to SARS-CoV-2 will confer immunity against re-infection and, if so, for how long? Will humans who recover from this infection be protected against a future exposure to the same virus months or years later? Knowing the duration of the antibody response to SARS-CoV-2 vaccines will also help to determine whether, and how often, booster immunizations will be needed if the initial response exceeds the protection threshold . It is clear that some candidate vaccines will have low efficacy , some vaccines will have high efficacy , and some will decline over time and will need booster doses. An updated list of the vaccines in development can be found in the WHO draft landscape of COVID-19 candidate vaccines.As of August 2020, among the ~25 COVID vaccines in advanced development, five had entered Phase III clinical studies, led by Moderna/NIAID, Oxford University/Astra Zeneca, Pfizer/ BioNTech, Sinopharm, and Sinova Biotech.20 Most of these candidates are intended to induce antibody responses that neutralize SARS-CoV-2, thereby preventing the virus from entering target cells and infecting the host. In some cases, the vaccines may also induce antibody and/or cellular immune responses that eliminate infected cells, thereby limiting the replication of the virus within the infected host . The induction of neutralizing antibodies directed against the SARS-CoV-2 spike glycoprotein is considered a priority. The immunogens used to elicit neutralizing antibodies are various forms of the S protein, including the isolated receptor-binding domain . The S protein variants can be expressed in vivo from DNA or mRNA constructs or recombinant adenovirus or vaccinia virus vectors, among others. Alternatively, they can be delivered directly as recombinant proteins with or without an adjuvant or as a constituent of a killed virus vaccine . Many of these approaches are included among the hundreds of vaccine candidates now at the pre-clinical and animal model stages of development. Antibody responses in COVID-19 patients vary greatly. Nearly all infected people develop IgM, IgG, and IgA antibodies against the SARS-CoV-2 nucleocapsid and S proteins 1–2 weeks after symptoms become apparent, and the antibody titers remain elevated for at least several weeks after the virus is no longer detected in the convalescent patient . The nature and longevity of the antibody response to coronaviruses are relevant to the potency and duration of vaccine-induced immunity. By far the most immunogenic vaccine candidates for antibody responses are recombinant proteins .