Immunity and vaccines
Immunity is all about recognition – it is the ability of the human body to recognize what is foreign as opposed to what is self. Material indigenous to the body is tolerated while foreign substances are eliminated. This discriminatory feature is due to a complex system of interacting cells called the immune system. The most effective immune responses are produced in response to antigens (usually proteins or polysaccharides) present in a live organism. The immune response includes the production of antibody, the activation of cytotoxic cells, or both, against the antigen.
Vaccination produces active immunity
There are two basic mechanisms of acquiring immunity – passive and active. When antibody produced by one animal or human is transferred to another, passive immunity is acquired by the recipient. A very common example is the passive immunity an infant receives from the mother. Passive immunity can also be generated through the transfusion of blood products containing certain amount of antibody. Passive immunity is short-lived, usually a few weeks to months.
On the other hand, active immunity is the protection against a disease by one’s own immune system. One way to acquire active immunity is to survive infection with the disease-causing form of the concerned organism. The resulting protection persists for many years, sometimes life-long,
Another way to produce active immunity is by vaccination. Antigens contained in vaccines stimulate the immune system. The consequent immune response is often similar to that by the natural infection. Gratifyingly, the recipient of vaccination is not subjected to the related disease or its associated predicaments.
Vaccines contain antigens
A vaccine is a biological product that can be used safely to induce an immune response in an individual. It is expected that the recipient would be protected against infection and/or disease on subsequent exposure to the concerned pathogen. To fulfil its purpose, the vaccine must contain antigens that are derived from the pathogen. Alternatively, it can be synthetically produced, say, by recombinant DNA technology.
Vaccines are generally classified as (a) live, attenuated, and (b) non-live (sometime referred to as “inactivated”). Live vaccines are derived from “wild” bacteria or viruses. Usually, these pathogens are attenuated (weakened) by repeated culturing in a laboratory. Although the attenuated vaccines replicate, they seldom cause disease.
Inactivated vaccines are not live and cannot replicate. These vaccines are unable to cause disease, even in an immunodeficient individual. However, the immunity they provide is not long-lasting. Evidently, multiple doses over time are needed for persistent immunity.
The antigenic component of non-live vaccines can be a killed whole organism, purified protein(s) from the organism, recombinant protein(s) or polysaccharides. Whole-cell inactivated vaccines contain bacteria or viruses that have been killed through a physical or chemical process.
Often, such vaccines are combined with a compound, known are adjuvant, to produce a more robust immune response. Based on their mechanisms of action, adjuvants have been broadly divided into delivery systems and immune-stimulators. Vaccines also contain other components that function as preservatives, emulsifiers or stabilizers.
Immune system – a complex network
It is well known that the immune system is a complex network of interacting cells. Lymphocyte cell types, such as T cells, B cells and plasma cells, and myeloid dendritic cells are the key players in the adaptive immune response process. These cells interact with each other through different molecules – T cell receptor (TCR), B cell receptor (BCR), pattern recognition receptor (PRR), and transmembrane proteins encoded by the major histocompatibility complex (MHC).
As the vaccine is injected into muscle, the protein antigen is taken up by dendritic cells. These cells are activated through PRRs by “danger signal” in the adjuvant and then trafficked into the lymph node. Here, the presentation of the vaccine antigen by MHC molecules on the dendritic cells activates T cells through TCR. Activated T cells drive soluble antigen-bound (through BCR) B cell development in the lymph node. The T cell-dependent B cell development results in maturation of the antibody response. Further, short-lived plasma cells, which secrete antibodies specific to the vaccine antigen, and memory B cells are produced. Thus, adaptive immune response is essentially mediated by B cells. T cells playing the role of a facilitator.
Generation of immune response to vaccine
Conventional vs mRNA
Conventional vaccines have been able to eradicate, or nearly eradicate, several life-threatening diseases such as small pox and polio. These are either based on whole inactivated virus (WIV) or target a pathogenic protein or its receptor binding domain (RBD). Yet, despite their noteworthy success, these vaccines have failed to effectively tackle pathogens such as the malaria parasite, hepatitis C and human immunodeficiency virus.
Over the past three decades, efforts have made to develop nucleic acid vaccines based on messenger RNA (mRNA). In principle, mRNA vaccines have certain important advantages over conventional vaccines. First, mRNA does not integrate into the genome; hence, the possibility of insertional mutagenesis is eliminated. Further, mRNA vaccines can be manufactured in a “cell-free” manner – this allows rapid, scalable and cost- effective production.
Initially, there were some concerns about the stability, poor efficacy and excessive immunostimulatory action of mRNA vaccines. Nonetheless, extensive research on mRNA pharmacology, effective delivery vehicles and controlling mRNA immunogenicity have made their clinical application viable.
mRNA-LNP-formulated vaccine
Vaccines containing synthetic mRNA
mRNA vaccines comprise synthetic mRNA molecules that direct cellular production of desired antigens. In vitro transcribed mRNA mimics the structure of endogenous mRNA. There are five sections in the molecule from 5¢ to 3¢ – 5¢ cap, 5¢ untranslated region (UTR), an open reading frame ((ORF) that encodes the antigen, 3¢ UTR and a poly(A) tail.
The 5¢ cap structure prevents unintended immune response as well as protects the mRNA from degradation by exonucleases. The 5′ and 3′ UTRs, which flank the coding region, regulate mRNA translation, half- life and subcellular localization. UTR sequences can be modified to minimize mRNA degradation.
Evidently, the most crucial component is the ORF. It contains the coding sequence that is translated into protein. The ORF can also be optimized to increase translation by replacing specific codons without altering the protein sequence.
mRNA is large and negatively charged – hence, it cannot pass through the lipid bilayer of cell membranes. Besides, inside the body it is swamped with cells of the innate immune system and degraded by nucleases. In vivo application, therefore, requires the use of mRNA delivery vehicles to transfect immune cells. However, such vehicles must not cause toxicity or unwanted immunogenicity.
Lipid-based nanoparticles
Lipid-based nanoparticles (LNPs) are the most clinically advanced mRNA delivery vehicles. Cationic lipids have been found to be highly effective at mRNA delivery. Nevertheless, they trigger toxic pro-apoptotic and pro-inflammatory responses. To overcome these safety issues, ionizable lipids have been developed as the most important components of LNPs. Three other lipid components – cholesterol, helper lipid and polyethylene glycol-attached (PEGlyted) lipid – also promote nanoparticle formation and function.
Appalled by the COVID-19 pandemic, vaccine development proceeded at an unprecedented speed. By December 2020, two vaccines – Pfizer-BioNTech’s BNT162b2 and Moderna’s mRNA-1273 – received US Food and Drug Administration’s emergency use authorization. These mRNA- based vaccines were found to be highly effective against SARS- CoV-2.
WIV vaccines for global equity
Nevertheless, mRNA vaccine platforms and production approaches fell short of achieving global COVID-19 vaccine equity. A vast majority of the world population had to rely on vaccines produced and scaled through the traditional (WIV) technology.
Three major WIV COVID-19 vaccines have been authorized for emergency use. Covaxin (Bharat Biotech) is a WIV vaccine created in collaboration with the Indian Council of Medical Research and the National Institute of Virology in India. Besides, two Chinese companies, Sinovac Biotech and Sinopharm, have manufactured CoronaVac and BBIBP-CorV respectively.
Not surprisingly, therefore, experts around the globe have suggested that research and development must continue in both mRNA- and WIV-based vaccine technologies. Only then the world can hope to sail through the present pandemic and be prepared for any future contingency.