The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from Wuhan in China has caused significant mortality and morbidity. The genome sequence of this virus, belonging to the Beta coronavirus genus, was first published on 11th January 2020, and showed that it is a single-stranded RNA virus containing 14 open reading frames (ORFs). These ORFs give rise to four major viral structure proteins: spike (S), membrane (M), envelope (E) and nucleocapsid (N) proteins. The S protein, which seems to play a major role in the viral entry into cells, has less than 75% sequence identity in SARS-CoV and SARS-CoV-2 and it is understood that this difference makes the SARS-CoV-2 more potent, with three additional short insertions in the N-terminal domain and changes to four out of the five amino acids in the receptor-binding domain (RBD). The S-protein of both the viruses bind to the same human cellular receptor-angiotensin converting enzyme II, but SARS-CoV-2 appears to be more readily transmitted from human to human.
The S-protein seems to be a major target for COVID-19 vaccine development aimed at neutralising the virus. Using publicly available sources, the Coalition of Epidemic Preparedness Innovations (CEPI) maintains an overview of the landscape of vaccine development.
Diversity of technologies
The global COVID-19 vaccine programme includes 115 vaccine candidates, of which 78 are confirmed as active programmes and the status of 37 is unknown. These are further categorized into 10 categories, namely, live attenuated virus, inactivated, non-replicating viral vector, replicating viral vector, recombinant protein, peptide-based, virus-like particle, DNA, RNA and unknown.
In terms of the status of vaccine development, there are three stages, i) phase I clinical trials ii) preclinical and iii) research stage. Some of the top vaccine research programmes in phase I clinical trials are those of: Moderna (mRNA-1273, NCT04283461), CanSinoBiologics (Ad5-nCoV, ChiCTR2000030906) and Inovio (INO-4800-DNA, NCT04336410). The preclinical stage vaccine molecules include those from: Pfizer and BioNTech (BNT162 mRNA), Novavax (recombinant nanoparticle vaccine), CureVac (mRNA-based), Generex (li-Key peptide vaccine), Vaxart (oral recombinant vaccine), Imperial College London (self-amplifying RNA vaccine), Medicago (plant based vaccine – VLP), J&J (AdVac abd PER.C6 systems) and Altimmune (intranasal vaccine).
Some of the new clinical trials registered are by Shenzhen Geno-Immune Medical Institute’s technology for using dendritic cells modified with a lentiviral vector expressing synthetic minigene based on domains of selected viral proteins (administered with antigen-specific CTLs – LV-SMENP-DC, phase I clinical trial NCT04276896) and aAPCs modified with a lentiviral vector expressing synthetic minigene based on domains of selected viral proteins (pathogen-specific aAPC – phase I clinical trial NCT04299724).
The most interesting feature of all these vaccine development programmes is the diversity of technologies which are under consideration. Some of these technologies are not typical of the vaccine field but their encouraging
value in oncology has led to the belief that they may play a role in developing novel approaches with faster development of vaccines. Potentially, some of the above vaccines might be limited to specific types of population such as immunocompromised patients, children, elderly and pregnant women.
One of the main reasons for faster vaccine development is that the viral cycle is limited to a maximum of 28 days. Previous studies with MERS-CoV, SARS-CoV and other coronaviruses have raised important concerns regarding S-protein based vaccines, such as immunological effects — including pulmonary eosinophilic infiltration and antibody-dependent disease enhancement (ADE) — after a viral challenge in vaccinated animals. Important observations on the stimulation of macrophages, increased levels of proinflammatory cytokines IL6, IL8 and MCP1, and reduced levels of TGF-beta involved in tissue repair are associated with ADE. Furthermore, inactivated virus-based vaccines have been shown to have Th2-associated immunopathology after the virus challenge. It is now proposed that instead of using the entire S-protein, a neutralising epitope of an S1 region called RBD may be a good alternative for vaccine development. It may be a challenge for present vaccine development programmes to address these adverse effects.
Adjuvants: Uncompromised safety
Moderna’s molecule mRNA-1273 was taken to clinical testing after just 2 months of sequence identification and will have to show how it will induce a strong immune response and maintain a high level of protein expression.
Some of the vaccine technologies may not be able to induce high immunogenicity and will need adjuvants to enable the vaccination of larger populations without compromising safety. Several companies such as GlaxoSmithKline, Dynavax and Seqirus have licensed their adjuvants such as AS03, CpG 1018 and MF9 for COVID-19 vaccine development programmes.
72% of vaccine development is presently undertaken by private industry and the rest by academic or public sector organisations. Of these, the majority of the developmental activity is in North America, followed by China, Europe and Australia. The vaccine development effort has been unprecedented and may become available under emergency use by early 2021. However, this time, the research community has taken an approach different from the traditional vaccine development mechanism which usually takes 10 years and more.
Industry benchmarks suggest that traditional vaccine development for licensed vaccines has an attrition rate of more than 90%. This shows the high risk associated with delivering a safe and effective licensed vaccine.
The most important step which will make this challenge formidable is to work together, across borders. Science has no borders and scientists must collaborate more in developing and delivering protection for the
entire world. It is time to form a coalition of humans and to speed up research and manufacture and deploy the solution at a scale large enough to guarantee access for every person on this earth.