Background Population movement could extend multidrug-resistant tuberculosis (MDR-TB) transmission and complicate its global prevalence. We sought to identify the high-risk populations and geographic sites of MDR-TB transmission in Shenzhen, the most common destination for internal migrants in China. Methods We performed a population-based, retrospective study in patients diagnosed with MDR-TB in Shenzhen during 2013–2017. By defining genomic clusters with a threshold of 12–single-nucleotide polymorphism distance based on whole-genome sequencing of their clinical strains, the clustering rate was calculated to evaluate the level of recent transmission. Risk factors were identified by multivariable logistic regression. To further delineate the epidemiological links, we invited the genomic-clustered patients to an in-depth social network investigation. Results In total, 105 (25.2%) of the 417 enrolled patients with MDR-TB were grouped into 40 genome clusters, suggesting recent transmission of MDR strains. The adjusted risk for student to have a clustered strain was 4.05 (95% confidence interval, 1.06–17.0) times greater than other patients. The majority (70%, 28/40) of the genomic clusters involved patients who lived in different districts, with residences separated by an average of 8.76 kilometers. Other than household members, confirmed epidemiological links were also identified among classmates and workplace colleagues. Conclusions These findings demonstrate that local transmission of MDR-TB is a serious problem in Shenzhen. While most transmission occurred between people who lived distant from each other, there was clear evidence that transmission occurred in schools and workplaces, which should be included as targeted sites for active case finding. The average residential distance between genomic-clustered cases was more than 8 kilometers, while schools and workplaces, identified as sites of transmission in this study, deserve increased vigilance for targeted case finding of multidrug-resistant tuberculosis.

c Antibody-dependent cell-mediated cytotoxicity (ADCC) bridges innate and adaptive immunity, and it involves both humoral and cellular immune responses. ADCC has been found to be a main route of immune protection against viral infections in vivo. Hemagglutinin (HA) of influenza virus is highly immunogenic and considered the most important target for immune protection. Several potent cross-reactive HA-specific neutralizing monoclonal antibodies (MAbs) have been reported, and their conserved neutralizing epitopes have been revealed, but there has been no report so far about ADCC epitopes on HA. Here we identified two dominant ADCC epitopes, designated E1 (amino acids [aa] 92 to 117) and E2 (aa 124 to 159), on HA of pandemic H1N1 influenza virus by epitope mapping of convalescent-phase plasma IgG antibodies from six H1N1-infected human subjects in China that exhibited different levels of ADCC activity. The E1 and E2 ADCC epitopes overlapped with immunodominant epitopes of HA. Depletion of purified patient plasma IgG antibodies with EBY100 yeast cells expressing E1 or E2 decreased the ADCC activity of the IgG antibodies. E1 and E2 sequences were found to be highly conserved in H1N1 strains but less so in other subtypes of influenza A viruses. Our study may aid in designing immunogens that can elicit antibodies with high ADCC activity. Vaccine immunogens designed to include the structural determinants of potent broadly neutralizing antibodies and ADCC epitopes may confer comprehensive immune protection against influenza virus infection.

Human respiratory syncytial viruses (RSVs) are classified into two major groups (A and B) based on antigenic differences in the G glycoprotein. To investigate circulating characteristics and phylodynamic history of RSV, we analyzed the genetic variability and evolutionary pattern of RSVs from 1977 to 2019 in this study. The results revealed that there was no recombination event of intergroup. Single nucleotide polymorphisms (SNPs) were observed through the genome with the highest occurrence rate in the G gene. Five and six sites in G protein of RSV-A and RSV-B, respectively, were further identified with a strong positive selection. The mean evolutionary rates for RSV-A and -B were estimated to be 1.48 × 10–3 and 1.92 × 10–3 nucleotide substitutions/site/year, respectively. The Bayesian skyline plot showed a constant population size of RSV-A and a sharp expansion of population size of RSV-B since 2005, and an obvious decrease 5 years later, then became stable again. The total population size of RSVs showed a similar tendency to that of RSV-B. Time-scaled phylogeny suggested a temporal specificity of the RSV-genotypes. Monitoring nucleotide changes and analyzing evolution pattern for RSVs could give valuable insights for vaccine and therapy strategies against RSV infection.

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Broadly neutralizing antibodies (NAbs) such as those generated in chronic human immunodeficiency virus type 1 (HIV-1) infection are considered a key component for an effective HIV-1 vaccine. Here, we measured NAb responses using a panel of 25 Env-pseudotyped viruses, including clade B, C, A, CRF07_BC and CRF01_AE strains, against plasma samples from 103 subjects in a former plasma donor cohort in central China, who were infected with HIV-1 clade B9 for at least 10 years and naïve to antiretroviral therapy at the time of sampling. We found that 64 % of samples (n566) neutralized at least half of the viruses tested and 2 % (n52) neutralized all of the viruses, while 5 % (n55) neutralized none of the viruses tested. Strikingly, 29 % of plasma samples (n530) neutralized .80 % of the viral strains tested, indicating the presence of broadly reactive NAbs in these patients. When the magnitude (geometric mean ID 50 titres, GMTs) or breadth of neutralization was assessed for correlation with CD4 count or plasma viral load, the only significant positive correlations were observed between viral load and neutralization magnitude (r50.2189, P50.0263) and between viral load and neutralization breadth (r50.1970, P50.0461). A moderate difference between progressors and long-term non-progressors was observed in both the breadth (P50.0316) and the potency (P50.0300). A significant difference was found in the GMTs between intra-clade and inter-clade strains (P,0.001). Heat-map analysis based on k-means clustering of plasma determined a statistically stable cluster of plasma with cross-reactive and potent neutralizing reactivity. These samples could provide physical biomaterials for further virological and serological studies from which useful insights into rational HIV-1 vaccine development and therapeutic design might be derived.

Amyloid-β peptide (Aβ) is recognized by many as the leading cause of Alzheimer's disease (AD), and Aβ oligomers play a major role in the early-onset form of AD. Recently, the application of passive immunization targeting Aβ has been investigated as a potential method of AD immunotherapy. We used a strain of monoclonal antibody against Aβ42 oligomers, designated A8, as an Aβ inhibitor to suppress Aβ aggregation and Aβ-derived cell toxicity in vitro, and as a passive immunotherapy approach to treat SAMP8 (senescence accelerated mouse sub-line P8) mice, an animal model of AD, in vivo. First, our results showed that pre-incubation of A8 with Aβ oligomers inhibited both the maturation of Aβ fiber and Aβ oligomer toxicity on SH-SY5Y cells. Second, learning and memory was improved through intraperitoneal administration of A8 in SAMP8 mice. Third, Aβ pathology was ameliorated with decreased Aβ oligomers and phospho-tau levels in SAMP8 mice. Our data suggest that our monoclonal antibody A8 may be a candidate as a potential immunotherapeutic agent in AD.

Identification of broadly cross-reactive HIV-1-neutralizing antibodies (bnAbs) may assist vaccine immunogen design. Here we report a novel human monoclonal antibody (mAb), designated m43, which co-targets the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (Env). M43 bound to recombinant gp140 s from various primary isolates, to membrane-associated Envs on transfected cells and HIV-1 infected cells, as well as to recombinant gp120 s and gp41 fusion intermediate structures containing N-trimer structure, but did not bind to denatured recombinant gp140 s and the CD4 binding site (CD4bs) mutant, gp120 D368R, suggesting that the m43 epitope is conformational and overlaps the CD4bs on gp120 and the N-trimer structure on gp41. M43 neutralized 34% of the HIV-1 primary isolates from different clades and all the SHIVs tested in assays based on infection of peripheral blood mononuclear cells (PBMCs) by replication-competent virus, but was less potent in cell line-based pseudovirus assays. In contrast to CD4, m43 did not induce Env conformational changes upon binding leading to exposure of the coreceptor binding site, enhanced binding of mAbs 2F5 and 4E10 specific for the membrane proximal external region (MPER) of gp41 Envs, or increased gp120 shedding. The overall modest neutralization activity of m43 is likely due to the limited binding of m43 to functional Envs which could be increased by antibody engineering if needed. M43 may represent a new class of bnAbs targeting conformational epitopes overlapping structures on both gp120 and gp41. Its novel epitope and possibly new mechanism(s) of neutralization could helpdesign improved vaccine immunogens and candidate therapeutics.