In a recent study posted to the journal Molecular Biology Reports, researchers illustrated the current progress and obstacles in the coronavirus disease 2019 (COVID-19) vaccine development.

Study: Current advances and challenges in COVID-19 vaccine development: from conventional vaccines to next-generation vaccine platforms. Image Credit: Sylfida/Shutterstock
Study: Current advances and challenges in COVID-19 vaccine development: from conventional vaccines to next-generation vaccine platforms. Image Credit: Sylfida/Shutterstock

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-driven COVID-19 pandemic has caused an unprecedented global public health catastrophe. COVID-19 management is critical due to its high transmission, death rates and socioeconomic consequences.

Vaccines are the most effective strategy to control and end the COVID-19 pandemic in the absence of SARS-CoV-2-specific therapies. Currently, several pharmaceutical manufacturers around the globe are striving to create potent vaccines to fight the ongoing COVID-19 pandemic.

About the study

In the present review, the scientists summarized basic techniques employed for the development of SARS-CoV-2 vaccine candidates and each vaccine’s mode of action, benefits, and drawbacks. The team also explored the application of nanomaterials and nanotechnology in the formulation of COVID-19 vaccines.

Findings and discussion

The results of the review show that the SARS-CoV-2 vaccine design comprises various processes such as selecting antigens, vaccine platforms, routes, and cycles of vaccination. The COVID-19 vaccines developed so far are directed towards the SARS-CoV-2 receptor-binding domain (RBD), spike 1 (S1)/S2 protein subunit, and S gene based on the experiences gained from the SARS and the Middle East respiratory syndrome-CoV (MERS-CoV) outbreaks. Various potent neutralizing monoclonal antibodies (nMAbs) targeting the SARS-CoV-2 RBD are under clinical trials.

Non-neutralizing Abs (NAbs) were generated against SARS-CoV-2’s membrane (M), envelope (E), and S proteins. Nevertheless, E and M proteins have never been investigated as vaccine targets against SARS-CoV-2 due to their low immunogenicity for humoral responses. The use of other structural proteins such as nucleocapsid (N) or non-structural proteins as vaccine antigens might induce far more stable T cell and humoral-mediated immune responses. This inference was due to the ambiguous role of the non-NAbs and Abs with insufficient neutralizing capacity in Ab-dependent enhancement (ADE) disease.

COVID-19 vaccines based on SARS-CoV-2 nucleic acid, protein subunit, and the inactivated virus cannot be given via the respiratory mucosa because of their necessity for potentially dangerous immune adjuvants and recurrent administration. On the contrary, the SARS-CoV-2 recombinant viral-vectored vaccines, mainly those based on the chimpanzee adenovirus (ChAd) and Ad type 5 (Ad5), were both highly effective and safe when delivered through the respiratory mucosa. A heterologous or homologous COVID-19 vaccination regimen was required to sustain the protection against SARS-CoV-2 due to the uncertainty of vaccine-induced protection in humans long-term.

Live attenuated vaccine based on Bacille Calmette-Guérin (BCG) was under investigation for its usage in COVID-19 prevention. However, live attenuated vaccines were more reactive than recombinant protein-based vaccines, and they can infect or revert the virulent strain in people with compromised immune systems. Inactivated COVID-19 vaccines can be easily manufactured and ramped up utilizing well-established infrastructure and methodologies. Unlike live attenuated vaccines, inactivated viral vaccines exhibit few safety concerns and deliver a broad spectrum of native viral antigens.

Nonetheless, adjuvants and several administrations were necessary to activate the immune system and ensure that these vaccinations were fully effective since entirely inactive viruses did not replicate. They were also poor stimulators for cytotoxic CD8+T cells. Such risks can be overcome by using TH1 cell skewing altered alum or other adjuvants such as CpG. Sinopharm is presently conducting a phase 3 study of BBIBP-CorV.

Preliminary clinical trials of recombinant viral vector vaccines indicated significant Ab and cell-mediated immune responses following a single dose of adenoviral vectored vaccines such as Ad26.CoV2. S and Ad5‐nCoV.  A phase 4 clinical trial is ongoing for the non-replicating ChAdOx1 nCoV-19 vaccine.

In SARS-CoV-2 protein subunit vaccines, a full-length viral S protein or RBD or a combination of RBD with a carrier protein was used. However, they only trigger humoral immune responses. Hence, they require adjuvants in the formulation and repeated administrations. A full-length recombinant SARS-CoV-2 S nanoparticle vaccine named Novavax is in the phase 3 trial. Virus-like particles (VLPs) were an excellent choice for COVID-19 vaccine manufacturing because of the lack of infectious genetic material and functional protein. Yet, they require repeated dosing and adjuvants similar to protein subunit and inactivated vaccines.

The messenger ribonucleic acid (mRNA)-based COVID-19 vaccines were more appealing than other COVID-19 vaccination techniques because of their minimal cost and quick manufacturing procedure. Nevertheless, they might be linked to adverse reactions (ADRs) because of their high immunological capacity. SARS-CoV-2 mRNA-based vaccines were manufactured by prominent biotechnology firms like CureVac, Moderna, Pfizer, and BioNTech.

Plasmid deoxyribonucleic acid (DNA) vaccines were not very immunogenic and thus required many doses and the use of an adjuvant. Additionally, they were associated with adverse effects such as dysplasia by prompting mutations in the host genome and the formation of anti-DNA Abs. Inovio Pharmaceuticals has designed a phase 1 clinical trial to assess the effectiveness of a synthetic DNA vaccine expressing the SARS-CoV-2 S protein.

Since vaccine development based on antigen-presenting cells (APCs) was too expensive and time-consuming for large-scale production, technology utilizing artificial antigen-presenting cells (aAPCs) was developed. Several preclinical and clinical trials have been ongoing for developing aAPCs-based COVID-19 vaccines. Extra cold chain requirements for cell-based vaccines and injection techniques impede large-scale implementation of these vaccines, chiefly because a satisfactory response requires repeated administration.

Nanoparticles (NPs) containing immune-regulating compounds and antioxidants can supply therapeutic agents to inflammatory sites, thus reducing inflammation, cytokine responses, and oxidative stress in COVID-19 patients. Since the size of SARS-CoV-2 was nanoscale, nanotechnology can be employed to combat COVID-19. Drug NPs can give novel and cost-effective COVID-19 therapy options by boosting bio-degradation and compatibility and being eco-friendly.

The MERS-CoV S protein-based NP vaccines with the adjuvant mixture of the matrix protein (M1) demonstrated effectiveness in reducing MERS-CoV multiplication in the lungs of mice in a trial on VLNPs in mice. The high titer of NAbs against S protein in mice implies that they were immune to the virus. Thus, virus-like NPs (VLNPs) with the S protein might be efficacious against MERS-CoV and SARS-CoV-2 as both viruses employ the same mode of infection and invasion into host cells.

Gold-based NPs (AuNPs) may be a viable approach for developing CoV vaccines as they can induce CD4+ T cell expression and eventually lead to tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) expression. However, the induction and generation of protective Abs and eosinophilic infiltration were unaffected by the AuNPs-adjuvanted toll-like receptor (TLR) vaccination in a study evaluating AuNPs and TLR agonists containing recombinant SARS-CoV-2 S in mice.

Polymer-based (PB)-NPs play a critical role in the VLNP anti-MERS-CoV development, which might mirror the virus’ function. As a result, utilizing PB-NPs to develop effective COVID-19 vaccines represents a focal point for further investigations.

To date, the best protection against SARS-CoV-2 is offered by RNA-based COVID-19 vaccines. Various preclinical studies examining the effectiveness and immunogenicity of lipid NP (LNP)-mRNA vaccines encoding the SARS-CoV-2 S protein or S RBD have been conducted. An experiment in mice found that the SARS-CoV-2 S protein RNA incorporated LNP vaccine boosted immune responses against SARS-CoV-2.

The benefits of employing NPs in vaccine manufacturing include the improvement of conjugated or adsorbed drugs antigenicity, the stimulation of adaptive and innate immunity, efficient controlled release properties, and cell targeting. However, the use of NPs in vaccines has some drawbacks including the requirement of adjuvant, multiple doses, lagged immune responses, and cellular toxicity.

The DNA, protein subunit, and inactivated COVID-19 vaccines exhibited fewer local and systemic ADRs than the granular, non-replicating vector, and RNA vaccines. Further, the highest adverse effects linked to reactogenicity were demonstrated by the mRNA-based COVID-19 vaccines. The most frequently reported local side effect of SARS-CoV-2 vaccines was injection site pain, and the common systemic ADRs included headache and fatigue.

Conclusions

The study findings depicted different strategies associated with SARS-CoV-2 vaccine development ranging from nucleic acids and protein subunits through VLPs. None of the COVID-19 vaccines developed so far imparted 100% protection against SARS-CoV-2 infection. Thus, even with vaccination, there was a potential of infection, although it will most likely be very mild or asymptomatic, with extremely low likelihoods of serious disease or death.

During pandemics like COVID-19, in addition to the general criteria for successful vaccine development, such as efficacy, safety, and duration of protection, the rapid production of a vaccine with a high generation capacity as well as distributing and administering the SARS-CoV-2 vaccine to vulnerable people, are all significant challenges. Constant mutational changes in the SARS-CoV-2 structure were another bottleneck in COVID-19 vaccine development.

Together, despite the high pace with which people are vaccinated against SARS-CoV-2 globally, the emergence of variants demonstrating significant immune escape raises questions about the existing vaccines’ effectiveness. Thus, novel COVID-19 vaccine research and development by companies and universities should be backed by strict proteomic and genomic surveillance. It helps to quickly identify SARS-CoV-2 mutations and scrutinize their effects on transmission rate, the severity of pathogenicity, and immune escape resulting in improved COVID-19 vaccine development and pandemic control.

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