Dengue genetic divergence generates within-serotype antigenic variation, but serotypes dominate evolutionary dynamics

Dengue virus (DENV) exists as four genetically distinct serotypes, each of which is historically assumed to be antigenically uniform. Recent analyses suggest that antigenic heterogeneity may exist within each serotype, but its source, extent and impact remain unclear. Here, we construct a sequence-based model to directly map antigenic change to underlying genetic divergence. We identify 49 specific substitutions and four colinear substitution clusters that robustly predict dengue antigenic relationships. We report moderate antigenic diversity within each serotype, resulting in genotype-specific patterns of heterotypic cross-neutralization. We also quantify the impact of antigenic variation on real-world DENV population dynamics, and find that serotype-level antigenic fitness is a dominant driver of dengue clade turnover. These results provide a more nuanced understanding of the relationship between dengue genetic and antigenic evolution, and quantify the effect of antigenic fitness on dengue evolutionary dynamics.

Dengue antigenic relationships predict evolutionary dynamics

Dengue virus (DENV) exists as four genetically distinct serotypes, each of which is historically assumed to be antigenically uniform. However, recent analyses suggest that antigenic heterogeneity may exist within each serotype, but its source, extent and impact remain unclear. Here, we construct a sequence-based model to directly map antigenic change to underlying genetic divergence. We identify 49 specific substitutions and four colinear substitution clusters that contribute to dengue antigenic diversity. We report moderate antigenic diversity within each serotype, resulting in variation in genotype-specific patterns of heterotypic cross-neutralization. We also quantify the impact of this antigenic heterogeneity on real-world DENV population dynamics. We find that antigenic fitness mediates fluctuations in DENV clade frequencies, although this appears to be primarily explained by coarser serotype-level antigenic differences. These results provide a more nuanced understanding of dengue antigenic evolution, with important ramifications for vaccine design and epidemic preparedness.Author SummaryDengue virus (DENV), the causative agent of dengue hemorrhagic fever, exists as four genetically distinct serotypes, DENV1 to DENV4. These serotypes are antigenically distinct: symptomatic reinfection with a homotypic virus is very rare, while reinfection with a heterotypic virus is sometimes associated with severe disease. Until recently, it has been assumed that viruses within each serotype are antigenically uniform. However, specific genotypes within each serotype have been anecdotally associated with varying severity of patient outcomes and epidemic magnitude. One hypothesis is that each serotype contains overlooked, meaningful antigenic diversity. While antigenic cartography conducted on neutralization titers suggests that heterogeneity may exist within each serotype, its source, extent and impact is unclear. Here, we analyze a previously published titer dataset to quantify and characterize the extent of DENV intraserotype antigenic diversity. We map antigenic changes to specific mutations inE, the dengue envelope protein, and interpolate across the alignment to estimate the antigenic distance between pairs of viruses based on their genetic differences. We identify 49 specific substitutions and four colinear substitution clusters that contribute to dengue antigenic evolution. We find that DENV antigenic divergence is tightly coupled to DENV genetic divergence, and is likely a gradual, ongoing process. We report modest but significant antigenic diversity within each serotype of DENV, which may have important ramifications for vaccine design. To understand the impact of this antigenic heterogeneity on real-world DENV population dynamics, we also quantify the extent to which population immunity—accumulated through recent circulation of antigenically similar genotypes—determines the success and decline of DENV clades in a hyperendemic population. We find that antigenic fitness is a key determinant of DENV population turnover, although this appears to be driven by coarser serotype-level antigenic differences. By leveraging both molecular data and real-world population dynamics, these results provide a more nuanced understanding of dengue antigenic evolution, with important ramifications for improving vaccine design and epidemic preparedness.

ANTIGENS OF SURFACE STRUCTURES OF HAEMOPHILUS INFLUENZAE AS PERSPECTIVE VACCINE-CANDIDATES

Despite long and successful use of Haemophilus influenzae b (Hib) vaccine, production of the vaccine against non-typed strains of Haemophilus influenzae (NTHi) is only being developed. Difficulties of this work are determined by features of NTHi compared with Hib: lack of polysaccharide capsule, high level of antigenic heterogeneity and specialties of pathogenesis development that includes spread through the organism from mucosa of the respiratory tract. Currently, 15 surface structures of NTHi are being actively studied with the aim of creating the vaccine. PE, P2, P6, PD proteins, outer membrane vesicles (OMVs) and others are among them. Only PD protein currently has practical application, that was used as a carrier with antigenic function in conjugated polysaccharide vaccines against pneumonia (Prevenar; PHiD-CV). Vaccination with these preparations allowed to reduce the total morbidity with acute rhinitis on children by 33 - 52%. However, this result can not be examined as final, thus, research and approbation of the vaccine-candidates continues.

The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin

TheTreponema denticolaFhbB protein contributes to immune evasion by binding factor H (FH). Cleavage of FH by theT. denticolaprotease, dentilisin, may contribute to the local immune dysregulation that is characteristic of periodontal disease (PD). Although three FhbB phyletic types have been defined (FhbB1, FhbB2, and FhbB3), thein vivoexpression patterns and antigenic heterogeneity of FhbB have not been assessed. Here, we demonstrate that FhbB is a dominant early antigen that elicits FhbB type-specific antibody (Ab) responses. Using the murine skin abscess model, we demonstrate that the presence or absence of FhbB or dentilisin significantly influences Ab responses to infection and skin abscess formation. Competitive binding analyses revealed that α-FhbB Ab can compete with FH for binding toT. denticolaand block dentilisin-mediated FH cleavage. Lastly, we demonstrate that dentilisin cleavage sites reside within critical functional domains of FH, including the complement regulatory domain formed by CCPs 1 to 4. Analysis of the FH cleavage products revealed that they lack cofactor activity. The data presented here provide insight into thein vivosignificance of dentilisin, FhbB and its antigenic diversity, and the potential impact of FH cleavage on the regulation of complement activation.

Results of Detection Antibodies against Rickettsiae in the Blood Sera at the Omsk Region of Russia and the West-Kazakhstan Region of Republic Kazakhstan

Previously, we found high species- and antigenic heterogeneity of spotted fever group rickettsiae circulating in the territories of the Russian Federation. This paper presents the results of the detection of antibodies to R. sibirica and R. conorii by using of complement fixation test and indirect immunofluorescent test (IFT) in the sera of patients after tick bites in tick-borne rickettsioses foci in border areas of Russia and Kazakhstan. The results of the study allow us to recommend carrying out the serological study of the blood sera of patients after tick’s bites using IFT with antigens of Rickettsia species, which circulation is proved or suspected in the area.