COVID-19 vaccines: The status and perspectives in delivery points of view

Abstract

Due to the high prevalence and long incubation periods often without symptoms, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected millions of individuals globally, causing the coronavirus disease 2019 (COVID-19) pandemic. Even with the recent approval of the anti-viral drug, remdesivir, and Emergency Use Authorization of monoclonal antibodies against S protein, bamlanivimab and casirimab/imdevimab, efficient and safe COVID-19 vaccines are still desperately demanded not only to prevent its spread but also to restore social and economic activities via generating mass immunization. Recent Emergency Use Authorization of Pfizer and BioNTech's mRNA vaccine may provide a pathway forward, but monitoring of long-term immunity is still required, and diverse candidates are still under development. As the knowledge of SARS-CoV-2 pathogenesis and interactions with the immune system continues to evolve, a variety of drug candidates are under investigation and in clinical trials. Potential vaccines and therapeutics against COVID-19 include repurposed drugs, monoclonal antibodies, antiviral and antigenic proteins, peptides, and genetically engineered viruses. This paper reviews the virology and immunology of SARS-CoV-2, alternative therapies for COVID-19 to vaccination, principles and design considerations in COVID-19 vaccine development, and the promises and roles of vaccine carriers in addressing the unique immunopathological challenges presented by the disease.

Keywords: Coronavirus disease 2019 (COVID-19); Immune response; Neutralizing antibodies; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Vaccine delivery.

Graphical abstract

Fig. 1

Current pre-and clinical trials of COVID-19 vaccines, according to World Health Organization (WHO) as of December 8, 2020. Out of 214 vaccine candidates, 52 are in clinical trials and 162 are in pre-clinical studies. The lead vaccine candidates target the SARS-CoV-2 spike (S) protein including the receptor binding domain (RBD) subunit, followed by full length S protein.

Fig. 2

Structure of SARS-CoV-2 with a positive-sense, single stranded RNA that shares 79.6% sequence identity to SARS-CoV and encodes the S, M, E and N proteins. The S protein, a major target for vaccination, contains three critical elements: S1, receptor binding domain (RBD), and S2 subunits. The S1 subunit contains the N-terminal and the C-terminal subdomain (CTD) that are in a closed conformation until specific proteases cleave the S1/S2 and S2’ sites. The RBD is located in the S1-CTD and necessary for binding to the ACE2 receptor on the surface of the host cells. The S2 subunit domain forms a trimeric structure and contains the fusion peptide (FP) and two heptad repeats (HR1 and HR2) which are required for the fusion of viral and host membrane. The most abundant N protein packages the genome into a virion for effective viral replication, the M protein is involved in viral integration, and the E protein facilitates assembly, envelope formation, and budding.

Fig. 3

Immune response to SARS-CoV-2 at varying pathological stages. In stage 1, in the nasal cavity, SARS-CoV-2 binds to ACE2 receptors on epithelial cells by the S protein, enters the cell, and starts to replicate. The virus proliferates and simultaneously travels down the respiratory tract, and clinical manifestation of symptoms start appearing. Upon infection, the virus activates type I IFNs. In COVID-19 patients, type 1 IFN production is delayed by SARS-CoV-2, which lowers the adaptive immune response. The host innate immune system detects SARS-CoV-2 via recognition of pathogen-associated molecular patterns (PAMPs) by the alveolar macrophages activating cytokines such IL-6 and TNF-α leading to phagocytosis of the virus or activation. In stage 2, infected epithelial cells present viral antigens to both CD4⁺ and CD8⁺ T cells. CD8⁺ T cells release perforins and granzymes that induce apoptosis of the infected cells. CD4⁺ T cells rapidly activate to become Th1 cells that secrete GM-CSF and further induce monocytes by high IL-6 levels. An increase in monocyte subpopulation promotes IL-1β production. Th17 cells produce IL-17 to further recruit monocytes, macrophages, and neutrophils, and stimulates other inflammatory cytokines such as IL-6, IL-1, and IL-1β. In stage 3, inflammatory cells release additional cytokines which amplifies the cytokine storm and exacerbates the systemic inflammatory response, eventually leading to ARDS, multiorgan failure, and death.

Fig. 4

Schematic representation of SARS-CoV-2 infection and signaling pathways as potential targets for treatment. SARS-CoV-2 binds to ACE2 and TMPRSS2 receptors through the S protein resulting in viral-host membrane fusion. Umifenovir and camostat mesylate inhibit the fusion process of viral entry. Virus enters the cells by endocytosis, and chloroquine and hydroxychloroquine inhibit the endosomal acidification and interfere with glycosylation of ACE2. The viral RNA is released and translated to essential viral polyproteins, 3CLpro and PLpro. Lopinavir/Ritonavir inhibits the activity of 3CLpro. Viral replication requires the RNA polymerase and remdesivir incorporates into nascent viral RNA causing RNA synthesis arrest, preventing viral replication. SARS-CoV-2 infection induces a massive release of cytokines including IL6, IL-1β, and IL-1 and increases the activation of NF-κB and JAK-STAT signaling pathways. Tocilizumab and sarilumab bind to membrane and soluble IL-6 receptors suppressing the JAK-STAT signaling pathway and attenuating inflammatory processes. Baricitinib and ruxolitinib inhibit the kinase activities of JAK1 and JAK2 and anakinra, an IL-1 receptor antagonist, reduces hyperinflammation and respiratory distress.

Fig. 5

SARS-COV-2 structure, infection, and cellular processing. SARS-CoV-2 binds to ACE2 and TMPRSS on the epithelial cell surface via the S protein which mediates virus-cell membrane fusion and entry. Viral genomic RNA is released and translated into viral polymerase proteins. Viral RNA is replicated and reverse transcribed in the cytoplasm, and the transcribed and translated viral proteins are transported into the endoplasmic reticulum (ER) and the Golgi. The S, E, and M protein are assembled in the ER-Golgi compartment and form a mature virion. The N protein assembles with mature virion, and a whole virus is released. The S, E, M, and N proteins are degraded into peptides and the viral antigens are presented by MHC I and II to CD8⁺ T and CD 4⁺ T cells, respectively, to induce cellular and humoral immunity.

Fig. 6

Molecular and viral vaccines post-injection act as a depot site, necessitating uptake by local cells for antigen presentation. Vaccines from this category require recruitment of APCs (e.g., DCs) to the vaccination site for subsequent antigen processing and transportation to the lymph nodes. Importantly, these vaccine formulations typically include adjuvant for immune stimulation including desired DC maturation. Nanoparticle formulations also accompany adjuvant and ensure the co-delivery of both adjuvant and the vaccine payload to DCs, resulting in increased likelihood of DC maturation against the co-delivered antigens. Targeting moieties also assist nanoparticles in reaching the DC. DCs can also be isolated and engineered ex vivo to present SARS-CoV-2 antigens for the optimized antigen presentation in a desired maturation state. While this process is time-consuming, expensive, and difficult, direct deployment of antigen presenting DCs avoids pharmacokinetic (PK) and pharmacodynamic (PD) barriers, such as clearance associated with molecular and viral vaccines, and the cell recruitment steps required by other vaccination methods. Activated DCs migrate through the lymphatics to the lymph node where they can educate T and B cells for active clearance of infected cells and antibody production.

Fig. 7

Clinical disease development of COVID-19 and combined vaccination and treatment strategy for synergistic SARS-CoV-2 eradication, minimized side effects, and lowered mortality. Within 1-2 days post infection, SARS-CoV-2 locally replicates, and most individuals are asymptomatic. In the following 3-7, the virus continues to spread to the respiratory tract and the lungs with clinical manifestation. Inflammatory cells release high levels of cytokines (e.g., IL-6, IL-1β, and IFNα), contributing to a cytokine storm. In the later stages of infection, COVID-19 patients become severely ill, leading to ARDS, multiple organ failure, and eventually death. Most treatment interventions have focused on repurposed anti-viral or anti-inflammatory drugs and the FDA approved the use of remdesivir and dexamethasone for inhibition of viral RNA synthesis and to dampen inflammation, respectively. Controlling both virus replication and inflammation can help reduce patient mortality rate but their clinical efficacy is limited. Diverse nanotechnology platforms can be designed for combination therapy by the delivery of multivalent antigens and desired drugs which can synergistically reduce viral load, inflammation, and severe disease progression.