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Background: With limited severe acute respiratory syndrome coronavirus (SARS-CoV-2) testing capacity in the United States at the start of the epidemic (January-March 2020), testing was focused on symptomatic patients with a travel history throughout February, obscuring the picture of SARS-CoV-2 seeding and community transmission. We sought to identify individuals with SARS-CoV-2 antibodies in the early weeks of the US epidemic., Methods: All of Us study participants in all 50 US states provided blood specimens during study visits from 2 January to 18 March 2020. Participants were considered seropositive if they tested positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies with the Abbott Architect SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) and the EUROIMMUN SARS-CoV-2 ELISA in a sequential testing algorithm. The sensitivity and specificity of these ELISAs and the net sensitivity and specificity of the sequential testing algorithm were estimated, along with 95% confidence intervals (CIs)., Results: The estimated sensitivities of the Abbott and EUROIMMUN assays were 100% (107 of 107 [95% CI: 96.6%-100%]) and 90.7% (97 of 107 [83.5%-95.4%]), respectively, and the estimated specificities were 99.5% (995 of 1000 [98.8%-99.8%]) and 99.7% (997 of 1000 [99.1%-99.9%]), respectively. The net sensitivity and specificity of our sequential testing algorithm were 90.7% (97 of 107 [95% CI: 83.5%-95.4%]) and 100.0% (1000 of 1000 [99.6%-100%]), respectively. Of the 24 079 study participants with blood specimens from 2 January to 18 March 2020, 9 were seropositive, 7 before the first confirmed case in the states of Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi., Conclusions: Our findings identified SARS-CoV-2 infections weeks before the first recognized cases in 5 US states., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Aims: To assess the influence of chemical treatment of the anode of a marine sediment biofuel cell (MSBFC) on the microbial diversity of the anode biofilm., Methods and Results: A MSBFC was equipped with two graphite plate anodes, one pretreated by electrochemical oxidation in sulfuric acid and the other untreated. After 6 weeks of operation, 16S rRNA clone libraries were constructed from each anode biofilm. The pretreated anode exhibited a fourfold depletion in gamma-proteobacteria, a fourfold enrichment in delta-proteobacteria, a sixfold increase in sulfate reducers, a fivefold enrichment in unclassified micro-organisms, and 6% of the colonies were sulfur oxidizers while none were detected on the untreated anode., Conclusion: Anode pretreatment significantly affects the anode-colonized microbial communities of MSBFCs., Significance and Impact of the Study: The MSBFC is one of a new class of microbial fuel cells in which the anode is spontaneously colonized by a subset of micro-organisms indigenous to a complex anaerobic mixture (such as sewage and food processing effluents). These micro-organisms utilize the anode as an oxidant, catalysing power generation by oxidizing fuel in the mixture and reducing the anode. This study reveals that pretreatment of the anode can greatly affect the composition of the microbial colony of such fuel cells.

Background: Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a major structural viral protein, can confer protection against subsequent experimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 VLP vaccine in healthy adults., Methods: Volunteers were given intramuscular injections with placebo or with 10- or 50-microg doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HPV16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the reciprocals of the highest dilution showing positive reactivity in each assay. All statistical tests were two-sided., Results: The prevaccination geometric mean ELISA titer for six seropositive individuals was 202 (range, 40--640). All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant. With the higher dose, the geometric means of serum ELISA antibody titers (95% confidence intervals) to purified VLP 1 month after the third injection were as follows: 10,240 (1499 to 69 938) without adjuvant, 10,240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum. Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation =.85), confirming that ELISA titers are valid proxies for neutralizing antibodies., Conclusions: The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.

Papillomavirus-like particle (VLP)-based subunit vaccines have undergone rapid development over the past 8 years. Three types are being investigated. The most basic type is composed of only the L1 major capsid protein and is designed to prevent genital human papillomavirus (HPV) infection by inducing virus-neutralizing antibodies. On the basis of positive results in animal models, clinical trials of this type of vaccine for HPV16, and other types, are currently under way. Preliminary results have been encouraging in that systemic immunization with the L1 VLPs induced high serum titers of neutralizing antibodies without substantial adverse effects. The second type of vaccine incorporates other papillomavirus polypeptides into the VLPs as L1 or L2 fusion proteins. These chimeric VLPs are designed to increase the therapeutic potential of an HPV vaccine by inducing cell-mediated responses to nonstructural viral proteins, such as E7. Studies in mice indicate that these vaccines generate potent antitumor cytotoxic lymphocyte (CTL) responses while retaining the ability to induce high-titer neutralizing antibodies. It is likely that prophylactic and therapeutic clinical trials of chimeric VLPs will be initiated in the near future. The third type of VLP-based vaccine is designed to induce autoantibodies against central self-antigens by incorporating self-peptides into the outer surface of VLPs, a process that could have therapeutic potential in various disease settings unrelated to HPV infection. In a recent proof of concept study, a peptide from an external loop of mouse CCR5 protein was inserted into a neutralizing epitope of L1. In mice, the particles generated by this chimeric L1 were able to induce high titers of CCR5 antibodies that specifically recognized the surface of CCR5-transfected cells and blocked in vitro infection of an M-tropic human immunodeficiency virus strain.

A subset of human papillomaviruses (HPVs) has been implicated as the principal etiologic agents of cervical cancer. Cervical cancers consistently retain and express two of the viral genes, E6 and E7. Although infection with HPV seems to be necessary, other factors, such as cellular immune function, play an important role in determining whether cervical infection will regress, persist, or progress to cancer. The close relationship between viral infection and cancer makes HPV an attractive target for prophylactic and therapeutic vaccines. Candidate vaccines have been shown to have efficacy in animal models, and human clinical trials are planned or in progress.

There is strong epidemiologic evidence for sexual transmission of high-risk genital human papillomavirus (HPV) types. However, it is unclear if infection may also be transmitted indirectly via fomites. To assess this possibility, the in vitro infectivity after desiccation was compared for pseudotype HPV-16 virions, a model for high-risk type genital HPV, and bovine papillomavirus type 1 (BPV-1), a papillomavirus known to be transmitted via fomites. The 2 viruses had similar resistance to desiccation in cell extracts, retaining approximately 100%, 50%, and 30% of infectivity when dehydrated for 1, 3, and 7 days, respectively, at room temperature. Pseudotype HPV-16 and BPV in cell extracts were completely inactivated by autoclave treatment and susceptible to 70% ethanol but were resistant to EDTA or incubation at 56 degrees C for 1 h. The data suggest that further study of nonsexual spread of high-risk genital HPV via fomites is warranted.

Seroreactivity to human papillomavirus type 16 (HPV-16) virus-like particles (VLPs) in men attending clinics for sexually transmitted diseases (STDs) in Denmark (n = 219) and Greenland (n = 88) was compared with seroreactivity in women attending the same clinics and was furthermore related to epidemiologic variables and concurrent HPV DNA detection. Risk factors for male seropositivity in Denmark were lifetime number of sex partners, a history of STDs, and sexual preference and in Greenland were ever having had syphilis and years at school. Although men reported significantly more sex partners, the mean seroreactivity was significantly lower in men than in women: 0.50 and 0.75, respectively, in Denmark and 0.53 and 0.86 in Greenland (P = .0001). Male seropositivity was not correlated with concurrent HPV DNA detection, but only 15 Danish and 6 Greenlandic men had HPV-16 DNA. Presence of HPV-16 VLP antibodies appears to be a biomarker for exposure to genital HPVs in men but is less sensitive than in women.

The epidemiologic determinants of seroreactivity to human papillomavirus (HPV) type 16 L1/L2 virus-like particles (VLPs) were assessed separately in HPV-16 DNA-positive and -negative women participating in a nested case-control study of incident cervical neoplasia. Seventy-four women with cervical HPV-16 DNA and 656 cytologically normal HPV-16 DNA-negative subjects were interviewed and tested at two time points for viral DNA and once (at the later time) for VLP seroreactivity. Among subjects who were currently HPV-16 DNA-negative, seroreactivity odds ratios increased from 2.9 for 2-5 male sex partners (vs. 0 or 1) to 5.4 for 6-9 partners and 14.0 for > or = 10. Thus, prior cervical infection may be a major determinant of seroreactivity in HPV-16 DNA-negative women. This trend was not observed in HPV-16 DNA-positive subjects. Seroreactivity was independently associated with oral contraceptive use, particularly in HPV-16 DNA-negative subjects with use for > or = 10 years. Consequently, a possible role for virus-steroid hormone interactions in seroconversion is suggested.

Background: The existence of large geographic variations in the prevalence of esophageal cancer in some countries, such as China, indicates that environmental risk factors may be important in the development of this disease. Some studies have implicated genital-mucosal strains of human papillomaviruses (HPVs) in the etiology of this cancer., Purpose: We conducted a case-control study in Shaanxi Province, China, an area with a population at high risk for esophageal cancer, to assess the association of this disease with infection by HPV type 16 (HPV16), the most common cancer-associated genital-mucosal HPV type., Methods: Ninety individuals with esophageal cancer and 121 cancer-free control subjects were identified among the patients in two hospitals in Xi'an, Shaanxi Province. The control subjects were matched to the case patients on the basis of age and sex. Blood specimens were drawn from all study subjects, and serum was isolated by routine methods. The presence of HPV16 antibodies in serum samples was determined by use of an enzyme-linked immunosorbent assay (ELISA) that used baculovirus-derived HPV16 virus-like particles as the antigen. A similar ELISA that used bovine papillomavirus type 1 (BPV1) virus-like particles as the antigen controlled for the specificity of HPV16 seroreactivity. Data from the HPV16 and the BPV1 assays were normalized with respect to results obtained in each assay with a control serum of known HPV16 seroreactivity. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association between HPV16 seroreactivity and esophageal cancer. Reported P values are two-sided., Results: The mean seroreactivity to HPV16 virus-like particles was significantly higher for the cancer patients than for the control subjects (mean value +/- standard deviation = 0.85 +/- 0.22 versus 0.74 +/- 0.18; P<.0001). When the cancer patients and control subjects were compared by sex and age groups, the differences in mean seroreactivity remained statistically significant. The difference in mean seroreactivity to BPV1 virus-like particles between cancer patients and control subjects was not statistically significant (0.81 +/- 0.28 versus 0.88 +/- 0.32; P = .12); this result was not altered when sex and age groups were compared. By use of a cutoff point for HPV16 seropositivity that was established in studies of cervical neoplasia, 24% of the cancer patients were seropositive compared with 7% of the control subjects, yielding a sex- and age-adjusted OR of 4.5 (95% CI = 1.8-11.9). In general, the OR for esophageal cancer increased with increasing HPV16 seroreactivity., Conclusions and Implications: HPV16 infection may be a risk factor for esophageal cancer. Further studies of the association between HPV16 infection and the incidence of esophageal cancer are needed.

It is not known whether DNA sequence variants of human papillomavirus type 16 (HPV-16) are distinct serotypes. To examine this question, the reactivities of women's sera from Zaire (n = 97) and Denmark (n = 123) were compared in IgG-specific ELISAs based on virus-like particles (VLPs) composed of the L1 major capsid protein derived from an HPV-16 variant common in central Africa (Z-1194) or one common in northern Europe (114K). These L1s differ in seven amino acids. There was a strong correlation between reactivity in the two assays for both sets of sera (correlation coefficients, 0.73 and 0.85 for Zairian and Danish sera, respectively). In only 1 serum was there evidence for a specific reaction to one but not the other VLP variant. The results support the conclusion that the virions of strains Z-1194 and 114K are serologically cross-reactive.

An ELISA to detect serum IgG antibody response to human papillomavirus (HPV) type 16 virus-like particles (VLPs) was evaluated in a case-control study of cervical neoplasia, nested within a prospective cohort study. Subjects included 688 controls with continued normal cytology and 152 cases with confirmed incident squamous intraepithelial lesions who were tested for DNA for a broad spectrum of HPV types at cohort and follow-up of controls, 16.6% were seropositive compared with 30.8% and 52.4% of cases with low- and high-grade lesions, respectively. Of HPV-16 DNA-negative subjects, 16.5% were seropositive. Seropositivity increased from 22.2% in subjects who were HPV-16 DNA-positive by polymerase chain reaction once only (enrollment or follow-up) to 83.3% in those who were HPV-16 DNA-positive at both time points. These data imply that serum antibody to HPV-16 VLPs is a relatively sensitive indicator of persisting cervical HPV-16 infection.

A human papillomavirus (HPV) type 16 virus-like particle-based ELISA was used to assess antivirion immune responses in 300 women participating in cervical cancer case-control studies in Colombia and Spain. Virion IgG antibodies were detected in the sera of 51% and 59% of women with HPV-16 DNA-positive invasive cervical cancer and 81% and 73% of women with HPV-16 DNA-positive cervical intraepithelial neoplasia grade III (CIN III) in Colombia and Spain, respectively. Capsid antibodies were detected in 22% and 3% of cancer controls (P < .001) and in 43% and 10% of CIN III controls (P = .010) from Colombia and Spain, respectively. Since Colombia has an 8-fold higher incidence of cervical cancer, these results demonstrate an association between ELISA positivity and cancer risk. Capsid antibody responses did not correlate with humoral responses of the same women to HPV-16 E6 and E7 oncoproteins.

Background: Previous studies have demonstrated that genital infection with high-risk types of human papillomavirus (HPV), most often HPV16, is the most significant risk factor for the development of cervical cancer. However, serologic assays that have been developed to identify high-risk HPV infection have either failed to associate serum reactivity with other indicators of HPV infection or have identified only a minority of HPV-infected individuals., Purpose: Our purpose was to determine whether a specifically developed enzyme-linked immunosorbent assay (ELISA) could detect IgG anti-HPV16 virion antibodies in the sera of women who had tested positive for genital HPV16 infection by DNA-based methods., Methods: An ELISA was developed using newly developed HPV16 virus-like particles as antigens to detect anti-HPV16 virion IgG antibodies. These particles are comprised of HPV16 structural proteins that are self-assembled in insect cells after expression by recombinant baculoviruses. The sera of 122 women, whose HPV status had been previously evaluated by nucleic acid-based methods, were tested by this ELISA., Results: The sera of 59% of women (32 of 54) positive for genital HPV16 DNA by polymerase chain reaction (PCR) were positive in the ELISA assay compared with sera from women who had tested negative for HPV DNA (P < .0005). In contrast, 6% of HPV DNA-negative women (two of 31) and 9% of women positive for low-risk HPV6/11 DNA (one of 11) were ELISA positive by this criterion. The sera of women who were DNA positive for two additional high-risk HPV types were evaluated; the sera of 31% of HPV18-positive (four of 13) and 38% of HPV31-positive women (five of 13) were positive in the HPV16 particle ELISA. The sera of 75% of HPV16 DNA-positive women with severe dysplasias (12 of 16) gave positive ELISA results. The sera of 67% of women (28 of 42) who tested positive for HPV16 DNA by both PCR and the less sensitive ViraType assay tested positive in the ELISA compared with 33% of women (four of 12) who were positive by PCR but negative by ViraType (P < .05)., Conclusion: The majority of women with cervical HPV16 infection generate an IgG antibody response to conformationally dependent epitopes of HPV16 L1 that can be detected by ELISA., Implication: This particular ELISA, or a similar one incorporating virus-like particles of additional HPV types, may be useful in determining the natural history of high-risk HPV infection and perhaps help to identify women at risk for developing cervical cancer.