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A strategic approach to COVID-19 vaccine R&D
(Extracted from Science Magazine)

Written by Dr KVRNS Ramesh, Associate Dean & Chairperson and Dr Hemant Yadav, Associate Professor, Dept. of Pharmaceutics, RAK College of Pharmaceutical Sciences

There is an urgent necessity to manufacture and distribute large number of safe and effective vaccine doses to immunize an extraordinarily large number of individuals in order to protect the entire global community from the continued threat of morbidity and mortality from severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2). The global need for vaccine and the wide geographic diversity of the pandemic require more than one effective vaccine approach. Collaboration will be essential among biotechnology and pharmaceutical companies, many of which are bringing forward a variety of vaccine approaches. The full development pathway for an effective vaccine for SARS-CoV-2 will require that industry, government, and academia collaborate employing innovative approaches each adding their individual strengths.

It is not yet clearly established as to what constitutes a protective immune response against COVID-19. Data from SARS-CoV-1 patients as well as recently infected SARS-CoV-2 patients document relatively high levels of immune responses after infection, especially antibody responses to the surface (spike) protein that mediates entry into host cells. However, in vivo data on the type or level of immunity required to protect from subsequent re-infection, and the likely duration of that protection, are currently unknown. In animal models of SARS-CoV-1, immunization with recombinant subunit proteins and viral- and nucleic acid–vectored vaccines, as well as passive transfer of neutralizing antibodies to the spike protein, have been shown to be protective against experimental infection. Endpoints vary from protection of infection to modification of viral replication and disease. These data bring optimism that a highly immunogenic vaccine will elicit the magnitude and quality of antibody responses required for protection. A high degree of safety is a primary goal for any widely used vaccine, and there is theoretical risk that vaccination could make subsequent SARS-CoV-2 infection more severe. This has been reported for feline coronaviruses and has been observed in some vaccine-challenge animal models of SARS-CoV-1. Animal models of SARS-CoV-2 infection are currently being developed, and these models can be used to better understand the immune responses associated with protection.

CLINICAL AND IMMUNOLOGICAL ENDPOINTS

The primary endpoint for defining the effectiveness of a COVID vaccine also requires discussion. The two most commonly mentioned are (i) protection from infection as defined by seroconversion and (ii) prevention of clinically symptomatic disease. This requires the close evaluation of the effect of vaccination on the severity of COVID-19 disease in a wide variety of epidemiological and medical settings among both younger and elderly populations as well as underserved minorities. Achieving these endpoints could also be associated with reduced transmissibility on a population basis.

Primary endpoints that involve reduction of disease require greater numbers of enrollees into trials, given that asymptomatic infection is estimated to be 20 to 40% of total cases of COVID-19. A major challenge leading to a degree of complexity in developing clinical trial protocols for serological endpoints is the lack of precise knowledge of incidence rates. A critical requirement for such a multi-trial strategy is the establishment of independent laboratories with similar or identical validated serologic assays to provide a harmonizing bridge between multiple vaccine products and multiple vaccine efficacy trials. Parameters that would distinguish the immune response resulting from vaccination versus the immunity developed after infection are under intense investigation and there is an immediate need to develop assays to address this issue.

More prolonged follow-up of the initial vaccine cohorts should be undertaken because the likelihood of SARS-CoV-2 reexposure is much higher than that of SARS-CoV-1. In spite of high mutation rate in SARS virusesmajor alterations in the spike protein are not extensive to date this enables cautious optimism that vaccines designed now will be effective against circulating strains 6 to 12 months in the future.Although the risk of severe disease or death in young healthy individuals from COVID-19 is quite low, it is not zero, and there are no proven effective therapies for COVID-19 to rescue volunteers with complications from such a challenge. It is also likely that on the contrary, a SARS-CoV-2 challenge strain will, by design, cause mild illness in most volunteers and thus may not recapitulate the pulmonary pathophysiology seen in some patients. Moreover, partial efficacy in young healthy adults does not predict similar effectiveness among older adults Whether such experiments may be worthy of pursuit or would have a beneficial impact on timelines for vaccine development needs careful evaluation by an independent panel of ethicists, clinical professionals and experts on vaccine development.

VACCINE PLATFORMS

It is encouraging that vaccine development efforts have moved swiftly and several major vaccine platforms are moving toward clinical evaluation. These include traditional recombinant protein, replicating and non-replicating viral vectors and nucleic acid DNA and mRNA approaches. Each of these vaccine platforms has advantages and limitations. Important characteristics include speed and flexibility of manufacture, safety and reactogenicity, durability of immunity, scale and cost of manufacturing, vaccine stability, and cold chain requirements. No single vaccine or vaccine platform alone is likely to meet the global need, and so a strategic approach to the multi-pronged endeavor is absolutely critical.

Several companies are developing nucleic acid–based vaccines, including Moderna, BioNTech/Pfizer, CuraVac (mRNA-based), and Inovio (DNA-based). DNA and mRNA based vaccines can be generated quickly on the basis of viral sequence, which allows a rapid pathway to the clinic. mRNA vaccines use lipid nanoparticles to protect and deliver the mRNA and effectively adjuvant the immunogen. The scalability of these lipid nanoparticles and their temperature stability are issues that need to be addressed. As such, the path forward is filled with optimism, but some uncertainty remains, requiring rapid assessment of these products’ immunogenicity and safety.Traditional recombinant protein technology can be used to express the spike protein (e.g., Sanofi,Novavax), but the time required to establish cell lines needed for manufacturing is longer than for nucleic acid vaccines. However, there exists a robust commercial experience with protein and protein particle vaccines, Protein vaccines will require a potent adjuvant and the availability of certain adjuvants may be limited.

STRATEGIC COLLABORATIONS

Under the ACTIV public-private partnership, National Institute of Health,USA, has partnered with its sister agencies in the Department of Health and Human Services, including the Food and Drug Administration, Centers for Disease Control and Prevention, and Biomedical Advanced Research and Development Authority; other U.S. government departments representatives from academia, philanthropic organizations, more than 15 biopharmaceutical companies and the Foundation for NIH. This forum allows for discussions and consensus on vaccine trial designs, rapid data sharing, and close collaborations between the public and private sectors to rapidly and efficiently conduct vaccine efficacy studies. A common Institutional Review Board as well as a common cross-trial Data and Safety Monitoring Board (DSMB) should be used so that the regulatory framework for the entire enterprise is coordinated and the regulatory agencies and the public can make objective assessment of the effect sizes between approaches.

Harmonized master protocols will be needed to enable transparent evaluation of the relative effectiveness of each vaccine approach. Data should be shared among companies and be provided to independent statistical evaluation, allowing the early evaluation of a potential surrogate marker of protection, which would markedly speed licensure and distribution. Innovations in the process of vaccine development are required to achieve the rapid development of the platform technologies entering clinical trials. Global effort, global cooperation, and transparency are needed to maximize the speed, veracity, and decision-making required to deliver scientific advances to the global population in a timely fashion. Models for all of these programs exist, and rapid implementation of these ideas is essential if we are to succeed in the timelines required to return us to pre–COVID-19 social interactions.

SCALE UP

The ability to manufacture hundreds of millions to billions of doses of vaccine requires the vaccine-manufacturing capacity of the entire world. Although new technologies and factories can be developed to sustain production, there is an immediate need to fund the necessary bio-manufacturing infrastructure. Cost, distribution system, cold chain requirements, and delivery of widespread coverage are all potential constriction points in the eventual delivery of vaccines to individuals and communities. All of these issues require global cooperation among organizations involved in health care delivery and economics.To return to a semblance of previous normality, the development of SARS-CoV-2 vaccines is an absolute necessity. To achieve this goal, all the resources in the public, private, and philanthropic sectors need to participate in a strategic manner.

References

1. Science Reference No:Science 10.1126/science.abc5312 (2020);

2. Retrieved from https://science.sciencemag.org/content/early/2020/05/12/science.abc5312