The rise of the COVID-19 pandemic has placed the need for effective vaccines and vaccine research into the global spotlight. As of May 19th, there are 133 SARS-CoV-2 vaccines in different stages of development (https://milkeninstitute.org/covid-19-tracker). With numerous institutions and companies currently focusing research efforts on the development of a safe and effective vaccine against SARS-CoV-2 and protection from the devastating effects of COVID-19 disease, it is an opportune time to discuss the similarities and differences in the classes of vaccines and the development process.
Effective vaccines, regardless of class, help protect the body against infection by activating the immune system and creating immunological memory to help the body fight future infections of same or similar organisms. There are two components to the immune system: (1) The innate immune response ; and (2) The adaptive immune response; both of which act in concert to provide protection from an invading pathogen. The innate response is the body’s first line of defense. It is a non-specific response induced by pathogen associated molecular patterns (PAMPs). These can be of extracellular origin, as in the case of bacterial lipopolysaccharide or intercellular origin, as in the case of viral dsRNA replicative intermediates. Recognition of PAMPs leads to a cascade of events that may include complement system activation, opsonization and phagocytosis, cytokine release, and inflammation.
The adaptive immune response is “learned” immunity that is specific to a pathogen. It is composed of two arms, the humoral response and the cellular response. The humoral response, represented by B-cells, is the antibody-mediated immunity arm while the cellular response, represented by CD4-helper T-cells and CD8-cytotoxic T-cells is the cell-mediated immunity arm. As the names imply, CD4-helper T-cells help promote cell-mediated (Th-1 cells) and antibody-mediated immunity (Th-2 cells) and CD8-cytotoxic T-cells promote killing of infected cells. Activation of the adaptive response results in the clonal selection and expansion of both B-cells and T-cells that are specific for the invading pathogen. Central to the ability of the adaptive immune response to provide protective immunity is that small population of these clonally-selected B- and T-cells that persist as memory cells long after infection; thus providing a source of pre-programmed immune cells for rapid response to subsequent infection or exposure to the offending pathogen.
There are six different classes of vaccines currently in development for SARS-CoV-2. The classes are:
- Live attenuated vaccines: These are a debilitated laboratory generated version of the original pathogenic organism. This class of vaccine, represented by vaccines to measles, mumps and chicken pox, typically produce robust long-term cellular and humoral immunity with one or two doses. While quite effective, since these vaccines are composed of replication competent viruses, there is the possibility of reversion back to the pathogenic form and they cannot be administered to immunocompromised patients. There are currently 3 live attenuated vaccine candidates in the pre-clinical stage of development for SARS-CoV-2. Two of these are codon “de-optimized” versions of SARS-CoV-2, and the third is an attenuated measles virus-based vaccine expressing SARS-CoV-2 antigen.
- Inactivated virus vaccines: These vaccines are infectious virus that have been inactivated by heat, chemicals or UV-irradiation. Examples of this class of vaccine include the yearly influenza vaccine. Since they are non-replicating these vaccines produce weaker immune responses than the attenuated viral vaccines and require additional booster shots to maintain immunity. Inactivated vaccines can also be used as booster challenges to primary vaccination with viral vector vaccines when immunogenicity to the viral vector may be a concern. There are currently 7 inactivated virus vaccines in the development pipeline for SARS-CoV-2, 3 in clinical phases and 4 in the pre-clinical phase.
- Protein subunit vaccines: As the name suggests, these vaccines contain a virally-encoded protein, or portion thereof, that can elicit an immune response. An example of this class of vaccine is the recombinant hepatitis B vaccine. These types of vaccines are generally designed to elicit a B- and T-cell response to essential viral epitopes on the surface of the virus. There are currently 41 SARS-COV-2 protein subunit vaccines in development, all in the pre-clinical phase.
- Nucleic acid vaccines: These vaccines are an alternative to conventional protein/peptide-subunit based vaccines, and are composed of nucleic acids (DNA or RNA) encoding viral antigens. Administration of these vaccines results in the uptake of the nucleic acid into a cell and expression of the encoded viral antigen by the host cells molecular machinery. There are currently no nucleic acid-based vaccines approved for use in humans, although there are several DNA-based vaccines that are approved for veterinary use. There are currently 11 DNA vaccines (one in clinical trials and ten in pre-clinical phase) and 18 RNA vaccines (two in clinical trials and 16 in pre-clinical phase) in development for SARS-CoV-2. While the concept of DNA vaccine technology has been around for over two decades, the development of RNA vaccines is a relatively recent event. One of the furthest advanced vaccines is the Moderna/NIAID RNA vaccine that is slated to begin Phase 2 clinical trials this month and enter Phase 3 in early summer.
- Viral vector vaccines (replicating and non-replicating): These vaccines use a viral genomic platform for a convenient way to deliver heterologous viral antigens to select target cells. A wide variety of replicating and non-replicating vectors are available as platforms. Replicating viral vectors have characteristics similar to that of an attenuated live virus, while non-replicating vectors are able to infect a cell but are unable to produce a viable progeny virus. Examples of viral vector vaccines include Ebola virus vaccines built on a replication competent VSV platform. There are currently 12 replicating (all pre-clinical) and 16 non-replicating (2 in clinical phase 14 in pre-clinical) viral vector vaccines in the SARS-CoV-2 development pipeline.
- Virus like particles (VLPs): These vaccine candidates are laboratory synthesized particles that are compositionally and structurally similar to that of the authentic viruses but lack the viral genome. VLP-based vaccines contain key viral antigenic epitopes and display immunogenicity similar to those of traditional vaccines, but they lack the ability to replicate due to the absence of a viral genome, making them a safe template for vaccine development. Examples of VLP-based vaccines include the HPV vaccine Gardasil. There are currently seven VLP-based SARS-CoV-2 vaccines in pre-clinical development stages.
Regardless of the class of vaccine, it is necessary to ensure that the candidate vaccine is safe and capable of inducing an effective immune response to the pathogenic agent prior to advancing the candidate into clinical trials. This is achieved through the use of animal models. Several factors should be considered when choosing an appropriate animal system, such as its relevance to the human disease, the immune response, and the ability to measure the vaccines effectiveness in producing protective immunity. Since viral pathogens have host specificity, it is difficult to find an animal model that precisely reproduces all the human disease phenotypes; however, animal model systems have been established for many viral pathogens that have proved effective for the development of vaccines and antiviral therapeutics.
At Noble Life Sciences, we have years of experience with multiple classes of vaccines and animal models in vaccine development. With GLP and non-GLP study capabilities we can be your pre-clinical vaccine development partner to help you design and execute your development program.