The European Centre for Disease Prevention and Control (ECDC) anticipates an initial shortage of vaccine and predicts that countries will need to identify priority groups for vaccination, with broad characterization to further categorize them into different priority tiers. A functioning vaccine is considered essential to containing the pandemic, in addition to current non-pharmaceutical interventions (such as physical distancing) and antivirals.^[19]

The German Standing Committee on Vaccination (STIKO) recommends to first vaccinate persons above the age of 80 years as well as persons living in retirement and nursing homes. The STIKO also recommends the vaccination of healthcare personnel and persons working in nursing homes.^[20]

The World Health Organization (WHO) Strategic Advisory Group of Experts on Immunization (SAGE) recommendations for COVID-19 similarly focus on the prioritization of vaccination for high-risk groups and provides a detailed “values framework” for fair vaccine distribution.^[21]

The U.S Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommendations for COVID-19 currently emphasize the following goals for a limited COVID-19 vaccine supply:^[22]

• “Decrease death and serious disease as much as possible
• Preserve functioning of society
• Reduce the extra burden the disease is having on people already facing disparities
• Increase the chance for everyone to enjoy health and well-being”

In addition to this, the CDC ACIP COVID-19 recommendations specify groups who should be prioritized for early vaccination in the case of limited COVID-19 vaccine supply. These are:^[22]

• “Healthcare personnel
• Workers in essential and critical industries
• People at high risk for severe COVID-19 disease due to underlying medical conditions
• People 65 years and older”

The EMA states that COVID-19 vaccines are being developed following the same legal requirements for pharmaceutical quality, safety and efficacy as other medicines. The EMA’s pharmaceutical legislation ensures that vaccines are approved only after scientific evidence has demonstrated that their overall benefits outweigh their risks.^[23] In view of the pandemic, the EMA and regulatory agencies in Europe are diverting resources to speed up processes and reduce timelines for the evaluation and authorization of COVID-19 vaccines.^[23]

The U.S. FDA has rigorous scientific and regulatory processes in place to facilitate development and ensure the safety, effectiveness and quality of COVID-19 vaccines.^[24] Guidance for Industry published in June 2020 gave recommendations on the data required to facilitate the clinical development and licensure of COVID-19 vaccines.^[25]

• COVID-19 vaccines licensed in the U.S. must meet the statutory and regulatory requirements for vaccine development and approval, including for quality, development, manufacture, and control.^[25]
• COVID-19 vaccine development may be accelerated based on knowledge gained from similar products manufactured with the same well-characterized platform technology, to the extent legally and scientifically permissible.^[25]
• As there are no accepted surrogate endpoints that are reasonably likely to predict clinical benefit of a COVID-19 vaccine, the goal of development programs should be to pursue traditional approval via direct evidence of vaccine safety and efficacy in protecting humans from SARS-CoV-2 infection and/or clinical disease.^[25]

The Medicines & Healthcare products Regulatory Agency (MRHA) have announced regulatory flexibilities in the UK.^[26],[27]

• This includes expedited scientific advice, and rapid reviews of clinical trials applications to support manufacturers and researchers on potential treatments for COVID-19.^[26]
• A temporary authorization to supply an unlicensed vaccine could be given by the UK’s licensing authority under regulation 174 of the Human Medicines Regulations.^[27] On December 2nd, 2020 the MHRA authorized BNT162b2 under these conditions.

The WHO has developed “WHO Target Product Profiles for COVID-19 Vaccines,” a document that provides guidelines for vaccine researchers, developers, manufacturers, and funding agencies on preferred outbreak and long-term COVID-19 vaccine characteristics. These profiles include details on safety, efficacy, and accessibility considerations for low- and middle-income countries.^[28]

• The preferred safety/reactogenicity profile recommended in “WHO Target Product Profiles for COVID-19 Vaccines” should have “safety and reactogenicity sufficient to provide a highly favorable benefit/risk profile in the context of observed vaccine efficacy; with only mild, transient adverse events (AEs) related to vaccination and no serious AEs.” Additionally, the document specifies that there should be no contraindications, and the vaccine should be well tolerated and effective for use in individuals of all ages as well as pregnant and lactating women.^[28]

• Furthermore, the preferred efficacy profile recommended is “at least 70% efficacy (on population basis, with consistent results in the elderly),” with a preferred durability of protection of at least 1 year.^[28]
• Regarding accessibility considerations during outbreak conditions, WHO emphasizes the “capability to rapidly scale-up production at cost/dose that allows broad use, including in low- and middle-income countries (LMIC),” while in the long term, it recommends the “availability of sufficient doses at cost/dose that allows broad use, including in low- and middle-income countries.”^[28]

The “ideal” COVID-19 vaccine candidate

Based on current immunological evidence, an ideal COVID-19 vaccine candidate will elicit a targeted anti-viral immune response including a TH1-biased cellular response, generation of neutralizing antibodies, and CD8 T cells.^[9],[29]

As with any anti-viral vaccine, an ideal COVID-19 vaccine candidate will be designed to leverage the inherent biological processes of natural adaptive immune responses, including specificity to appropriate antigenic epitopes and induction of long-lasting immune memory.^[9],[29]

• The immunological memory (memory B cells and T cells) generated by a vaccine grants those vaccinated the ability to quickly respond to subsequent exposures to the same or similar pathogen and to eliminate the pathogen (in a fraction of the time of a natural infection) with no or minimal symptomology.^[30]

Intramuscular injection of the vaccine will activate the innate immune system (i.e., dendritic cells (DCs) and other antigen-presenting cells (APCs)), stimulating further immune responses at the injection site (i.e., secretion of cytokines and recruitment of additional immune cells) and in the draining lymph nodes, where APCs activate some antigen-specific B cells and T cells.^[29],[31]

The expressed antigenic protein is then processed into peptides, which are presented on major histocompatibility (MHC) class I and II molecules of APCs to CD8 and CD4 T cells, respectively, stimulating expansion of the immune response, including generation of neutralizing antibodies and cytotoxic T-cell responses, as well as production of memory B cells and T cells.^[29],[31]

• TH1 (T-helper 1) CD4 T cells secrete anti-viral cytokines (including IFN-g, TNF-a, TNF-B, and IL-2) which help activate B cells and CD8 T cells.^[29]
• Anti-viral neutralizing antibodies, produced and secreted by B cells after appropriate stimulation, are important for restricting productive infection by binding to free/unbound virus particles in the body and preventing their binding and entry into target cells.^[29]
• CD8 T cells (also known as cytotoxic T lymphocytes, CTLs) identify and eliminate virus-infected cells directly by their secretion of perforin and granzymes.^[17] Perforin perforates the infected cell’s membrane, thus allowing for the entry of granzymes which enter the cell and stimulate the cell’s caspase cascade resulting in apoptosis/programmed cell death. CD8 T cells can also mediate other anti-viral effects (such as inhibition of viral entry and replication) through the secretion of IFN-g and TNF-a.^[29],[31]