In the absence of other effector proteins or cells, antibodies have the ability to inhibit viral entry into target cells in vitro. The presence of neutralizing antibodies in the serum of vaccinated individuals has been shown to be one of the associations in which most licensed vaccines work. Some viruses show considerable sequence variations in their surface proteins that are somehow associated with neutralizing antibodies, which in turn trigger a neutralizing antibody response targeting this mutant strain.
The ideal vaccine induces antibodies that neutralize most, if not all, of circulating antibodies to these viral families, and such antibodies are called broadly neutralizing antibodies (bnAbs).Although they differ in their characteristics and functions, bnAbs generally function by targeting epitopes that are highly conserved and exposed to mutable viral surface proteins. Conserved epitopes are usually found in variants of the same virus species, but the same conserved epitopes have recently been found in several different species of viruses in the family Paramyxovirus.
Immunodominance/immunoprominence/immunoquiescence, the immunogenicity of conserved and exposed epitopes on the surface of the virus will determine the extent to which bnAb is induced by vaccination or after viral infection. Viruses that are highly variated but still express immunodominantly or immunoprominent conserved epitopes are more likely to cause a bnAb response. Conversely, highly variable viruses with an immunodominantly variable (mutate) epitope and a relatively immunoquiescent conserved epitope are more likely to cause a strain-specific neutralizing antibody response, or a weaker or even no bnAb response.
Viruses with immunodominant/immunoprominent conserved epitopes
Measles virus is a special case of the virus. Its surface glycoprotein (measles hemagglutinin) exhibits considerable sequence variability, but very successful vaccines have been developed. A conserved epitope that appears to be immune dominance overlaps with its receptor binding site and induces a robust neutralizing antibody response that defends against all known viral genotypes (neutralizing antibodies target the receptor binding site, thereby preventing the virus from binding to the receptor).
New research shows that some of the recently isolated monoclonal antibodies were able to neutralize the 1954 strain.
Viruses with immunoquiescent/immunoquiescent/immunosilencing conserved epitopes
Although such viruses usually cause a weak bnAb response through vaccination, some people do develop a strong reaction, especially if triggered by natural infection over a longer period of time. These individuals can produce bnAbs, which in turn help define conserved neutralizing epitopes on viral surface proteins, thus paving the way for rational vaccine design for highly antigenic variants.
Coronavirus on Human Immunodeficiency Virus (HIV)
The HIV envelope spike (Env) is a target for neutralizing antibodies and contains several conserved epitopes that can be targeted by the bnAb. On the functional Env spike, both variable (various) neutralizing epitopes and broad-spectrum neutralizing epitopes are exposed, however, the latter tend to be more hypoimmunogenic. This is because they have strict spatial limitations for antibody recognition (CD4 binding site, proximal outer region of the membrane) or because they are composed at least or partially of glycans (variable cyclic/glycan epitopes).
In general, the high density of N-linked telglycans on HIV Env is a major obstacle to antibody recognition and induction. The identified bnAb appears to overcome these hurdles by overcoming anomalous features, including abnormally high levels of somatic hypermutation (44% [amino acids]), high frequency of deletions and insertions (9 amino acids in length), and long CDR3 (34 amino acids more in length). It should also be noted that the native trimers are metastable and easily dissociate into the gp120 and gp41 subunits, revealing strain-specific neutralizing epitopes that tend to be immune dominant (of the gp120 and gp41 subunits).
Influenza Virus
The target of the neutralizing antibody is the surface protein hemagglutinin, which contains a head (HA1) and a stem (mostly HA2) region. Seasonal vaccines against the expected predominant strains of influenza are developed each year, but high levels of sequence diversity between strains have proven challenging for the design of universal vaccines (ideally, only one in a lifetime). Variations in hemagglutinin protein are predominantly in the head region, and neutralizing antibodies found against this immune-dominant region are usually strain-specific. The stem region is highly conserved compared to the head region, and most of the known extensive bnAbs recognize this region, although some recognize highly conserved sialic acid binding sites in the head region.
Stem-targeting bnAbs occur infrequently, possibly because hemagglutinin proteins are tightly packed on the surface of the virus, which may reduce access to broadly neutralizing epitopes in this region. Compared with HIV-1 bnAbs, influenza bnAbs have a shorter CDR3 length (26 more amino acids in length) and a lower mutation frequency (18% more [amino acids]) with few gene insertions or deletions.
Malaria (Plasmodium falciparum)
Although malaria is a parasite rather than a virus, it does show great antigenic variability. Although bnAb has not yet been identified, it is worth considering here. Malaria diversity is expressed by the processes present in the life cycle and the amount of genetic variability of each antigen.
Although many different approaches are considered, vaccines can be produced for specific stages of the life cycle. In the pre-erythrocytic stage, cyclosporozoite protein (CSP) is a relatively conserved target, but its immunogenicity has been found to be poor. In the hematologic phase, MSP-1, AMA1 and PfEMP1 are considered potential drug candidates. The latter targets are much more antigenically diverse, and recent studies have found conserved regions in this segment that can be used as targets for bnAbs.
It is not difficult to find that the conserved epitopes of immune antigens, which mainly induce broad-spectrum or broadly neutralized antibodies, usually have relatively low immunogenicity, and the variable (variant) or variable epitopes of immune antigens mainly cause strain- or strain-specific antibody responses, and the immunogenicity is strong.
This issue of SnapShot hopes to provide ideas for workers engaged in neutralizing antibody related research or vaccine designers to better solve medical bottlenecks and solve the problem of "stuck neck".
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Cell 155, October 24, 2013 ©2013 Elsevier Inc.
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