The COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is in its sixth year and is being maintained by the inability of current spike-alone-based COVID-19 vaccines to prevent transmission leading to the continuous emergence of variants and sub-variants of concern (VOCs). This underscores the critical need for next-generation broad-spectrum pan-Coronavirus vaccines (pan-CoV vaccine) to break this cycle and end the pandemic. The development of a pan-CoV vaccine offering protection against a wide array of VOCs requires two key elements: (1) identifying protective antigens that are highly conserved between passed, current, and future VOCs; and (2) developing a safe and efficient antigen delivery system for induction of broad-based and long-lasting B- and T-cell immunity. This review will (1) present the current state of antigen delivery platforms involving a multifaceted approach, including bioinformatics, molecular and structural biology, immunology, and advanced computational methods; (2) discuss the challenges facing the development of safe and effective antigen delivery platforms; and (3) highlight the potential of nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNP) as the platform that is well suited to the needs of a next-generation pan-CoV vaccine, such as the ability to induce broad-based immunity and amenable to large-scale manufacturing to safely provide durable protective immunity against current and future Coronavirus threats.
Coronaviruses comprise a vast group of viruses capable of causing a spectrum of illnesses, ranging from mild conditions like the common cold to more serious diseases such as Middle East Respiratory Syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV). The clinical manifestations of infections caused by these viruses are highly variable, spanning from asymptomatic cases to severe disease marked by pneumonia, respiratory distress, and fever. In extreme instances, the disease may advance to acute respiratory distress syndrome (ARDS), septic shock, and death resulting from multi-organ failure. Severe COVID-19, particularly in vulnerable populations like the elderly and individuals with underlying health conditions, has necessitated hospitalization and mechanical ventilation, overwhelming healthcare infrastructures and prompting national lockdowns and large-scale vaccination efforts.
Additionally, the long-term morbidity associated with COVID-19 is significant, with up to 10% of individuals, regardless of initial disease severity, developing long COVID. This chronic condition is characterized by persistent, multisystemic symptoms such as muscle pain, fatigue, and cognitive impairment. The exact mechanisms and immunopathology causing long COVID-19 remain areas of intense investigation. Therefore, a pan-Coronavirus vaccine capable of protecting individuals from disease and reducing the community spread of the virus could help mitigate the burden of disease caused by multiple coronaviruses, including SARS-CoV-2, MERS-CoV, and endemic HCoVs, potentially reducing severe illness, hospitalizations, and long-term complications such as long COVID.
The development of pan-Coronavirus vaccines that protect from the current and future SARS-CoV-2 variants necessitates a multifaceted approach, incorporating molecular and structural biology, immunology, and advanced computational methods. A key to the design of these vaccines is the identification of conserved regions across coronavirus families that can serve as targets for cross-reactive neutralizing antibodies and CD4+ and CD8+ T-cell immunity. The Spike (S) protein, especially its receptor-binding domain (RBD), has emerged as a primary target for neutralizing antibodies due to its critical role in virus entry into host cells. However, identification of other conserved epitopes remains a significant challenge and an area of active research. An effective pan-Coronavirus vaccine, by definition, needs to prevent severe disease and/or infection caused by all viruses within the coronavirus family. The current widely employed SARS-CoV-2 vaccines based solely on the spike glycoprotein were very effective in blunting the severity of the pandemic in its early stages, but waning immunity and antigenic variation between emergent strains have limited their utility. As a result, frequent boosting and updating of the vaccine to better match circulating virus strains are being used to address this limitation. So far, this strategy has not been able to disrupt the transmission cycle; hence, it is not a long-term solution to ending this pandemic or preventing future ones.
This article reviews clinical trial data gathered from public databases, scientific literature, and research announcements up to the current year, 2024. Focus is placed on the current state of antigen delivery platforms best suited for pan-Coronavirus vaccines, emphasizing the challenges and innovations in developing these vaccines that can provide durable immunity against current and future coronavirus threats, evaluating their immunogenicity, efficacy, safety, and cross-reactive potential against various coronavirus strains.
Research and development of pan-Coronavirus vaccines have utilized technology platforms such as protein subunits, viral vectors, mRNA, and nanoparticle technologies to deliver the antigen of interest. These platforms have shown promise in eliciting broad and robust immune responses in preclinical models. These delivery platforms being explored for pan-Coronavirus vaccine development are at the forefront of immunological research, leveraging cutting-edge science to create vaccines that are not only effective against multiple strains of coronaviruses but can also be rapidly developed and deployed in response to new viral threats. Below we will highlight the delivery platforms that have been proposed for effective pan-Coronavirus vaccines:
Protein subunit vaccines include pieces (subunits) of the virus (e.g., whole antigens and/or conserved peptides) to stimulate an immune response without introducing the whole virus. These protein-based pan-Coronavirus subunit vaccines are sufficient to teach the immune system to recognize and attack the virus but cannot cause disease since they are only a part of the virus proteome. In addition, immune responses can be targeted to specific viral proteins associated with protection and avoid responses against other proteins that could be ineffectual or deleterious.
Adjuvanted protein-based subunit vaccines constitute a significant category of vaccines. Subunit vaccines face specific challenges compared to other platforms, primarily due to the need for optimization in the production of each protein antigen. Among the most advanced COVID-19 subunit vaccines is Novavax’s NVX-CoV-2373 (marketed as Nuvaxovid), which is produced using insect cells and formulated with the Matrix-M adjuvant, derived from saponin. This vaccine includes the stabilized, full-length spike (S) protein in its prefusion conformation, designed for optimal antigenicity. Similarly, Sanofi-GSK’s vaccine VidPrevtyn Beta contains prefusion-stabilized S protein trimers of SARS-CoV-2, also produced in insect cells and combined with the AS03 adjuvant. Both vaccines have completed human clinical trials and have been authorized for use by the European Union. Recombinant protein vaccines are attractive candidates due to their excellent safety profiles, lack of genome integration risk, absence of live viral elements, and compatibility with immunocompromised individuals. Additionally, they exhibit high production efficiency and stability. In recent studies, seven vaccine formulations containing various combinations of the RBD antigens from SARS-CoV, MERS-CoV, and SARS-CoV-2 XBB.1.5, along with Alum and CpG55.2 adjuvants, were tested in animal models. Mice immunized with the trivalent RBD-based vaccine developed strong antibody responses against all three antigens and efficiently neutralized the corresponding pseudo viruses. To date, only a few protein-based pan-Coronavirus vaccines are being evaluated in clinical trials as detailed in Section 2.5 of this review.
Peptide-based vaccines with a carrier also constitute a significant category of vaccines. Through the combination of several peptides, the vaccines increase the likelihood of cross-reactive T- and B-cell responses, as well as create the possibility of using specific peptides to omit immunopathological pro-inflammatory sequences from the vaccine construct and focus the immune response toward critical epitopes (Figure 1). This also allows for flexibility as the peptides can be adjusted to include new epitopes for emerging coronavirus strains. Additionally, the use of peptides rather than the live virus means the vaccine is non-infectious. Since the components of the vaccine are also not redundant with the human genome, there is a significant decrease in the risk of triggering allergic or autoimmune responses. Compared to adjuvanted protein-based subunit vaccines, peptide vaccines have a faster development through automated peptide synthesizers, as well as a fast purification process. The carriers are also straightforward to produce. Both combined allow for standardized mass production of peptide vaccines in an economically feasible manner without bio-contaminants. When properly adjuvanted, the peptide-based vaccines have been proven to be highly immunogenic. However, the vaccines could also potentially be produced without an adjuvant, utilizing carriers like liposomes. The peptide-based vaccines have also been shown to have greatly improved stability, are water soluble, and have less of a need for cold storage. The development is slower than mRNA vaccines, though, due to the time needed for the optimization of peptide epitopes and the carrier. Mosaic-8b from CalTech is a notable example. The mosaic vaccine was engineered using a multivalent protein domain known as SpyCatcher, enabling it to display receptor-binding domains (RBDs) from both human and animal coronaviruses. These RBDs include those from Bat CoV RaTG13, Bat CoV SHC014, Bat CoV Rs4081, Bat CoV RmYN02, Bat CoV Rf1, Bat CoV WIV1, Pangolin CoV Pang17, and SARS-CoV-2, and are presented on a nanoparticle carrier. Additionally, SK Biosciences has advanced efforts toward developing a peptide-based vaccine by fusing RBDs from SARS-CoV-2, SARS-CoV-1, Bat CoV RaTG13, and Bat CoV WIV1 to a carrier protein, I53-50A.
Figure 1. Peptides to deliver next-generation PanCoVax vaccine candidates: A portion of an antigenic protein such as a peptide or polypeptide from coronavirus is used alone or a combination of peptides from different proteins and/or different v
