Improvement in vaccine immunogenicity and enhancing immune response

In this article, I briefly describe the methods to improve vaccine immunogenicity and enhance the immune response.

Table of Contents

Vaccines

A vaccine is a biological preparation that gives immunity to some infectious diseases. The administration of vaccines is called vaccination. Edward Jenner was an English physician and scientist who pioneered the concept of vaccines including creating the smallpox vaccine, the world’s first vaccine. Vaccination is the most effective method of preventing infectious diseases. Diseases like measles, mumps, diphtheria, pertussis (whooping cough), rubella (German measles), poliomyelitis, and tetanus have largely declined due to successful vaccination.

When developing a vaccine, several key factors need to be considered. The vaccine must be both safe and effective in preventing infections. The approach should be feasible and cost-efficient for the target population. Commonly used vaccines today include live but weakened organisms, inactivated (killed) bacterial cells or viruses, and protein or carbohydrate fragments (subunits) derived from the target pathogen.

Addition of a conjugate or a multivalent component

The vaccine preparations not including a live component, can’t induce a stronger immune response due to poor immunogenicity. Fusing a highly immunogenic protein, a conjugate to these weak vaccine immunogens can fix this issue. Moreover, extraneous proteins linked with strong immune activation can be added to the multivalent vaccine to elevate immune reactivity against a weakly immunogenic pathogen-associated antigen.

Haemophilus influenzae type b (Hib) causes bacterial meningitis in children. This infection induces deafness in children. A conjugate formulation of a Hib vaccine consists of type b capsular polysaccharide covalently linked to a sturdy immunogenic protein carrier, tetanus toxoid (figure 1). This conjugate Hib vaccine results in rapid decline in countries, which have introduced this. The conjugate of polysaccharides and proteins is more immunogenic than the polysaccharide alone. The polysaccharide-protein conjugate activates T helper cells and enables class switching from IgM to IgG. This vaccine can induce memory B cells but can’t induce memory T cells specific to the pathogen.

**Figure 1: A conjugate vaccine prepared with conjugating surface polysaccharide of Hib with a toxoid**

A conjugate of β-glucan (isolated from brown alga) and diphtheria toxoid is prepared to combat fungal infection. This vaccine induces antibodies in mice and rats that protect these animals from fungi Aspergillus fumigatus and Candida albicans. Immunocompromised patients often struggle with fungal infections. Developing immunizations or antibody-based treatments could help address the challenges posed by the toxicity of antifungal drugs and the rise of resistant strains, which is particularly critical in hospital environments.

Development of a multivalent vaccine

Subunit polysaccharide vaccines induce humoral immunity but are incapable of inducing cell-mediated responses. Vaccines should contain both immunodominant B-cell and T-cell epitopes. A vaccine must be delivered intracellularly to generate a CTL response. The peptides can be processed and presented via class-I MHC molecules. Antigens are incorporated into lipid vesicles to form liposomes (figure 2) or immunostimulating complexes (ISCOMs), which can deliver many copies of the antigen into cells.

**Figure 2: Liposomes and ISCOMS are prepared from antigenic peptides**

Liposomes and ISCOMs can be prepared from detergent-extracted antigens or antigenic peptides. Liposomes are made up of phospholipid bilayers and ISCOMs are made up of phospholipid monolayers. To prepare protein-containing liposomes, the proteins are mixed with a suspension of phospholipids under conditions that form lipid bilayer vesicles. The proteins are incorporated into the bilayer with the hydrophilic residues exposed. Membrane proteins from various pathogens, including ISCOMs and liposomes mimic endogenous antigens. They get processed by the endogenous pathway and are presented with class I MHC molecules. This induces a cell-mediated response (Figure 3).

**Figure 3: ISCOM delivers antigen into the cell**

Adjuvants

The substances added to vaccine preparations to enhance the immune response are called adjuvants. Most live and some killed vaccines contain innate response elements, which are the target point for adjuvants. These additives when mixed with pathogen-associated antigens, help the vaccine to be delivered to the immune system, Thus, this enhances general immune responsiveness.

Aluminium salts, or alum have been used as the only adjuvant in human vaccines. It enhances TH2 responses but is a weaker stimulator of T_H1 pathways. Alum is used as an adjuvant by combining it with the immunogen in an emulsion. Its primary role is believed to involve the gradual release of the antigen at the injection site, promoting prolonged stimulation of the immune response. Additionally, it may assist in attracting antigen-presenting cells and facilitating the formation of larger antigen complexes, which are more readily engulfed by these cells through phagocytosis.

New adjuvants

Virosome and AS04, are the two new types of adjuvants licensed for human vaccines. A virosome is used in the inflexal V influenza vaccine and the hepatitis A vaccine. It is a reconstituted virus envelope containing phospholipids and virus glycoproteins without genetic information. ASO4 is a derivative of lipopolysaccharide and contains an alum salt. It is naturally found on the surface of gram-negative bacteria. This adjuvant triggers PRR signaling that helps to encourage T_H1 pathway responses. It is currently used in vaccines against HPV and hepatitis B. The new adjuvants enhance the production of antibodies in vaccines and may have the advantage of eliciting far greater cell-mediated responses than the alum.

While adjuvants have advanced humoral immunity, very few, if any, effectively boost cellular immunity, particularly CD8⁺ T-cell responses. Akiko Iwasaki and her team at Yale have developed an innovative strategy designed to protect against sexually transmitted diseases and treat certain types of cancer. Her approach, known as “prime and pull,” involves using a subunit vaccine to trigger the immune response, followed by the localized administration of chemokines to attract memory cells.

Conclusion

The vaccine preparations not including a live component can’t induce a stronger immune response due to poor immunogenicity. Fusing a highly immunogenic protein, a conjugate to these weak vaccine immunogens can fix this issue.

Subunit polysaccharide vaccines induce humoral immunity but are incapable of inducing cell-mediated responses. Vaccines should contain both immunodominant B-cell and T-cell epitopes. Antigens are incorporated into lipid vesicles to form liposomes or immunostimulating complexes (ISCOMs), which can deliver many copies of the antigen into cells. Liposomes and ISCOMs can be prepared from detergent-extracted antigens or antigenic peptides.

Adjuvants are the substances added to vaccine preparations to enhance the immune response. Most live and some killed vaccines contain innate response elements, which are the target point for adjuvants.

Aluminium salts, or alum have been used as the only adjuvant in human vaccines. It enhances TH2 responses but is a weaker stimulator of T_H1 pathways. Alum is used as an adjuvant by combining it with the immunogen in an emulsion. Its primary role is believed to involve the gradual release of the antigen at the injection site, promoting prolonged stimulation of the immune response. Virosome and AS04, are the two new types of adjuvants licensed for human vaccines. A virosome is used in the inflexal V influenza vaccine and the hepatitis A vaccine. ASO4, a derivative of lipopolysaccharide, is currently used in vaccines against HPV and hepatitis B.