COVID-19 Vaccine Knowlege: What is a non-replicating vaccine?
In addition, non-replicating mRNAs can be used to produce RNA-related vaccines that involve mRNA sequences encoding pathogen-specific proteins (antigens) in host cells.
What is a non-replicating vaccine?
In non-replicating vaccines, immunogens used to induce pathogen-specific host immune responses include killed pathogens, purified or synthesized pathogen structures or recombinant pathogen products as antigens.
There are several types of non-replicating vaccines, including live vaccines, attenuated vaccines, inactivated vaccines, subunit and conjugate vaccines, and RNA vaccines.
In live attenuated vaccines, pathogens that infect humans are continuously passaged in vivo (animal embryos) or in vitro (cell culture). For example, in the measles vaccine, the live measles virus undergoes a series of passages in chicken embryos; and with each passage, the virus replicates in chicken cells more efficiently and loses replication in human cells.
Although the replication ability of live attenuated pathogens is mostly limited by human cells, there is still a rare level of replication risk, which can make pathogens more virulent through genetic mutations.
However, in order to obtain the required long-term protection, a booster dose of inactivated vaccine may be required.
In subunit vaccines, specific products of the target pathogen are used to induce an immune response. Generally, pathogen products used in subunit vaccines include purified or recombinant protein-inactivated bacterial toxins, or polysaccharides present on surface capsules.
In addition, a genetically engineered transgene encoding a vaccine antigen can be inserted into another virus or bacteria, and used as a vector to transfer the vaccine antigen to host cells and trigger a pathogen-specific immune response. These types of vaccines are called recombinant vaccines.
Conjugate vaccines are made by combining polysaccharide residues in the bacterial surface capsule with carrier proteins (such as diphtheria toxoid protein). In terms of mechanism, the bacterial part used in the vaccine does not produce a strong immune response alone. However, the combination of the bacterial part and the carrier protein induces a powerful and comprehensive immune response.
In RNA vaccines, mRNA is used as a template for the endogenous synthesis of the target pathogenic protein (antigen). The non-replicating mRNA vaccine contains 3’untranslated region (UTR), target antigen sequence and 5’UTR. Such vaccines do not include other protein sequences that induce self-amplification of the inserted mRNA sequence.
What is a non-replicating viral vector?
Several viruses, including adenovirus, adeno-associated virus, measles virus, and human influenza virus, are widely used as viral vectors. Viral vectors that have been genetically modified to make replication defective are called non-replicating vectors. Eventually, the virus attains an attenuated state, in which it can still trigger the required human immune response, but cannot replicate in human cells.
Adenovirus is often used as a viral vector to produce vaccines with replication ability and vaccines with replication defects. In humans, 57 adenovirus serotypes have been identified and further divided into 7 subgroups (A-G). Most adenovirus-based vaccines are prepared using adenovirus type 5 (Ad5).
Adenovirus-based vaccines can induce antibody-mediated and T-cell- mediated immune responses. However, the intensity of the response depends on the virus serotype used to produce the vaccine.
In order to produce a replication-deficient vector, the two early genes E1A and E1B of adenovirus were replaced with transgene (the insertion antigen of the target pathogen) expression cassette, thereby preventing the virus from replicating in the host cell. In addition, by genetically depleting the E3 and E4 genes of the adenovirus vector, the host cell-mediated elimination of adenovirus-infected cells and the instability of the transgene can be prevented.
Immune response to non-replicating vaccines
For replication-deficient vaccines, each virus particle used as a vector can only infect a single cell, and a transgene carried only once can be used to induce host cell immune responses.
Although more than one billion copies of the viral vector are used in a single-dose vaccine, failure to replicate can significantly reduce pathogen-specific immune responses. In order to achieve a strong and sustained immune response, more vaccine doses are required, and therefore, it takes longer to obtain the required protection.
However, non-replicating vaccines are very safe because the risk of disease outbreaks induced by vaccine antigens is very low. In addition, non-replicating adenovirus-based vaccines have been shown to induce strong CD8+ T cell-mediated and antibody-mediated immune responses.