Antibody response to an eight-site intradermal rabies vaccination in patients infected with Human Immunodeficiency Virus

Objective

To investigate the rabies virus neutralizing antibody response in HIV-1-infected patients with CD4+ cell count ≤200 cells/μL or >200 cells/μL after post-exposure prophylaxis using an eight-site intradermal rabies vaccination regimen.

Methods

In a prospective cohort study, 27 HIV-1 infected patients were recruited, none of which had a history of rabies vaccination. All patients provided informed consent and were separated into two groups according to their CD4+ cell count (patients with CD4+ counts of ≤200 cells/μL and patients with CD4+ counts of >200 cells/μL). All patients received Purified Chick Embryo Cell rabies Vaccine (PCECV) using a modified eight-site regimen in which 0.1 mL of vaccine was injected intradermally on each of days 0, 3, 7, 14, and 30 (8–8–8–8–8). CD4+ cell counts, HIV-1 viral load and rabies virus neutralizing antibody (RVNAb) concentrations as determined by the Rapid Fluorescent Focus Inhibition Test (RFFIT) were evaluated on blood samples taken on days 0, 3, 7, 14, 30, 90, 180 and 365 after vaccination.

Results

Of the 27 patients included in the study, 18 patients (67%) had CD4+ cell counts of >200 cells/μL and 9 patients (33%) had CD4+ counts of ≤200 cells/μL. No patients had detectable RVNAb concentrations on day 0. By day 14, all patients had adequate RVNAb concentrations (≥0.5 IU/mL). There was no statistically significant difference in RVNAb concentrations between the two groups on days 3, 7, 14, 30, 90, 180 and 365 after vaccination.

Conclusion

PCECV is immunogenic in HIV-1-infected patients with CD4+ cell counts below 200 cells/μL when administered in a modified eight-site intradermal PEP regimen.     

Immunologic and virologic response after tetanus toxoid booster among HIV-1- and HIV-2-infected Senegalese individuals.

Twelve HIV-1-infected, nine HIV-2-infected patients and eight HIV-negative subjects were given a 40IU booster dose of tetanus toxoid (TT). Blood was collected on days 0, 7 and 30 after immunization. Changes in HIV-1 or HIV-2 RNA load were evaluated by nested PCR. TT-IgG antibody levels were quantified by ELISA. CD4 cell counts as well as activation, memory and maturation markers of T lymphocyte subsets were determined by flow cytometry. The induction of apoptosis was investigated using 7-aminoactinomycin D (AAD) and propidium iodide (PI) staining. Proliferative responses to TT and pokeweed mitogen (PWM) were determined by the level of [(3)H] thymidine incorporation. Seven and 30 days after immunization, there was no detectable increase in HIV-1 or HIV-2 plasma load. There were also no changes in CD4 cell counts, CD69, HLA-DR and memory CD45RO or naive CD45RA antigens. Immunization did not increase the spontaneous apoptosis of peripheral blood mononuclear cells (PBMCs), CD4+ and CD8+ T cells subsets neither in controls nor in HIV-infected patients. Similarly, apoptosis induced in vitro by PWM or by the specific TT recall antigen did not vary during the study period. The proliferative response to PWM and to the TT recall antigen was decreased both in HIV-1- and HIV-2-infected patients compared to HIV-negative controls. Immunization significantly increased the TT-IgG levels in healthy controls and in HIV-infected patients. However, the anti-TT-IgG response, as measured by the fold-increase index between days 0 and 30, was significantly higher in healthy controls than in HIV-1- (P=0.036) and HIV-2-infected patients (P=0.003). In conclusion, we found no deleterious immunologic or virologic effect was detected in healthy HIV-1- and HIV-2-infected individuals after antigenic challenge with a TT booster. However, the response to TT vaccination was lower in HIV-1- and in HIV-2-infected individuals than in healthy HIV-negative controls.     

Antibody responses and HIV-1 viral load in HIV-1-seropositive subjects immunised with either the MF59-adjuvanted influenza vaccine or a conventional non-adjuvanted subunit vaccine during highly active antiretroviral therapy

OBJECTIVE: To study immunological and virological parameters in HIV-1-seropositive adults treated with highly active antiretroviral therapy (HAART) for at least 7 months after immunisation with MF59-adjuvanted (FLUAD, Chiron, Siena, Italy) or with non-adjuvanted (AGRIPPAL, Chiron) trivalent influenza vaccine. DESIGN: Blood samples, collected before and after vaccination, were analysed for the presence of antibodies against the vaccine antigens, for number of CD4+ T lymphocytes and HIV-1 RNA levels. RESULTS: Forty-four volunteers received FLUAD and 40 AGRIPPAL influenza vaccine. Thirty days after vaccination both adjuvanted and non-adjuvanted vaccines induced significant increases of anti-influenza virus antibodies. However, antibody titres found in volunteers receiving adjuvanted vaccine were in general significantly higher when compared with those found in the non-adjuvanted vaccine group. The requirements of the European Commission of influenza vaccine for a non-elderly adult population were always met by recipients of the adjuvanted vaccine, even in those with the lowest CD4+ cell counts (<200 cells/mmc). The subjects receiving the non-adjuvanted vaccine failed to met these requirements. The CD4+ T lymphocytes and plasma HIV-1 RNA levels remained stable in the long term, both in people receiving adjuvanted or non-adjuvanted vaccine. CONCLUSION: MF59-adjuvanted influenza induced a significant higher immune responses as compared with conventional vaccine in HIV-seropositive HAART-treated patients. Both vaccines were safe regarding HIV RNA viral replication and loss of CD4+ T lymphocytes.     

Humoral response to hepatitis B vaccination and its relationship with T CD45RA+ (naïve) and CD45RO+ (memory) subsets in HIV-1-infected subjects

HIV disease leads to defects in cell-mediated immunity, impairing the immune response to new and recall antigens. We studied 55 HIV 1-infected patients who received of recombinant DNA hepatitis B vaccine and 20 controls. The overall hepatitis B virus (HBV) seroconversion rate was 59%. The median CD4+ T cell count among responders was 452 cell/mm(3), higher than non-responders (359 cells/mm(3)). The HIV plasmaviral loads were higher in non-responders. We concluded that total T CD4 cell count, memory T CD4+ cells and lower plasma viral load among HIV-1-infected subjects treated with HAART could be used to predict the immune response to vaccination with hepatitis B vaccine. Thus, considering cost benefits, HVB vaccination should be preferentially provided to HIV-infected patients with T CD4 cells count over 450 cells/mm(3), preferentially whose under HIV replication controlled.     

Long-term increase of CD4+ central memory cells in HIV-1-infected individuals by therapeutic HIV-1 rgp160 immunization

OBJECTIVE: To evaluate functional potential and phenotypic markers in HIV-1-infected patients immunized with HIV-1 rgp160. METHODS: We assessed changes in T-cell phenotype and immune function in 12 HIV-1-infected individuals that were part of a therapeutic vaccine study from 1992 to 1995 [Sandstrom E, Wahren B. Therapeutic immunisation with recombinant gp160 in HIV-1 infection: a randomised double-blind placebo-controlled trial. Nordic VAC-04 Study Group. Lancet 1999;353(9166):1735-42]. The patients received 160mug HIV-1 rgp160 or placebo i.m. at baseline (day 0), and months 1, 2, 3, 4, 6, and thereafter every 3 months. Frozen peripheral blood mononuclear cells (PBMC) were retrieved from time points 0, 9, 12 and 24 months for phenotypic analysis utilizing flow cytometry. RESULTS: Up-regulation of immune activation markers HLA-DR and CD38 was observed at baseline and throughout the monitoring period on both CD4(+) and CD8(+) T cells in all patients, reflecting immune activation due to persistent high viral load. Further enhanced expression of activation markers was observed over time in the vaccine group, but not the placebo group. We also observed a consistent long-term increase of the CD4(+) central memory population (CD3(+)CD4(+)CD45RA(-)CCR7(+)) in the vaccinated group. CONCLUSIONS: Administration of eight doses of rgp160 in a year appeared to partially reverse some of the defects exerted by HIV-1 on the immune system. A combination of vaccination with effective antiretroviral therapy (ART) may thus represent an immunotherapeutic intervention for treatment of chronic HIV-1 infection. The improvement of a HIV-1-specific central memory population and HIV-1 antigen-specific CD4(+) lymphoproliferative responses may have contributed to the short-term improved survival reported in the vaccinated group.     

Relation of activation-induced deaminase (AID) expression with antibody response to A(H1N1)pdm09 vaccination in HIV-1 infected patients

The relevance of CD4+T-cells, viral load and age in the immunological response to influenza infection and vaccination in HIV-1 infected individuals has previously been pointed out. Our study aimed at assessing, in the setting of 2009 A(H1N1)pdm09 influenza vaccination, whether quantification of activation-induced deaminase (AID) expression in blood B-cells may provide additional indications for predicting antibody response to vaccination in HIV-1 infected patients with similar CD4+T-cell counts and age. Forty-seven healthy controls, 37 ART-treated and 17 treatment-naïve HIV-1 infected patients were enrolled in the study. Blood was collected prior to A(H1N1)pdm09 vaccination and at 1, 3 and 6 months after vaccination. Antibody titers to A(H1N1)pdm09 vaccine were measured by hemagglutination inhibition (HI) assay while the mRNA expression levels of AID were measured by quantitative real time PCR. Upon B-cell activation in vitro, AID increase correlated to antibody response to the A(H1N1)pdm09 vaccine at 1 month after vaccination in all individuals. In addition, the maximum expression levels of AID were significantly higher in those individuals who still carried protective levels of A(H1N1)pdm09 antibodies after 6 months from vaccination. No correlation was found between CD4+T-cell counts or age at vaccination or HIV-1 viral load and levels of A(H1N1)pdm09 antibodies. Assessing AID expression before vaccination may be an additional useful tool for defining a vaccination strategy in immune-compromised individuals at risk of immunization failure.     

Clinical experience of the 23-valent capsular polysaccharide pneumococcal vaccination in HIV-1-infected patients receiving highly active antiretroviral therapy: a prospective observational study

To assess the impact of vaccination with 23-valent pneumococcal polysaccharide vaccine on the risks for development of pneumococcal disease, all-cause community-acquired pneumonia, HIV progression, and mortality and immunologic and virologic responses among HIV-1-infected patients treated with highly active antiretroviral therapy (HAART), we conducted a 2-year prospective observational cohort study at a university hospital in Taiwan. A total of 305 HIV-1-infected patients who received 23-valent pneumococcal vaccine (vaccinees) and 203 patients who did not (non-vaccinees) were prospectively observed between 1 June 2000 and 31 October 2002. Changes of CD4+ and plasma viral load (PVL) from baseline to week 4 of vaccination were assessed in 31 randomly selected vaccinees. The incidence of pneumococcal disease and bacteremia of vaccinees was 2.1 per 1000 patient-years (PY) (95% confidence interval (95% CI), 1.7-2.5 per 1000 PY) over the median observation of 641 days (range, 37-832 days) following vaccination while that of non-vaccinee was 21.8 per 1000 PY (95% CI, 20.1-23.7 per 1000 PY) and 7.3 per 1000 PY (95% CI, 7.0-7.6 per 1000 PY), respectively, over the observation of 500 days (range, 32-851 days), with an adjusted odds ratio (AOR) for developing pneumococcal disease of 0.085 (95% CI, 0.010-0.735) and for bacteremia of 0.22 (95% CI, 0.018-2.561). The median CD4+ count increased by 45 x 10(6) l(-1) (P = 0.01) and median PVL change was 0 log(10) copies/ml (range of decrease, -0.74 to 2.47 log(10) copies/ml) after 1 month of pneumococcal vaccination among the subgroup of 31 vaccinees receiving HAART. The median CD4+ count increase from baseline to the end of study was 149 x 10(6) l(-1) for vaccinees and 107 x 10(6) l(-1) for non-vaccinees (P = 0.21). The AOR of developing all-cause community-acquired pneumonia and new AIDS-defining opportunistic illnesses (OI) of vaccinees as compared to non-vaccinees was 1.876 (95% CI, 0.785-4.485) and 0.567 (95% CI, 0.217-1.484), respectively. Death rate of vaccinees and non-vaccinees was 17.7 per 1000 PY (95% CI, 16.5-18.9 per 1000 PY) and 80.5 per 1000 PY (95% CI, 77.1-83.9 per 1000 PY), respectively. Adjusted hazard ratio for death of vaccinees as compared with non-vaccinees was 0.733 (95% CI, 0.236-2.274). Our data suggested that vaccination with 23-valent pneumococcal polysaccharide vaccine and receipt of HAART were associated with reduced risks for pneumococcal disease among HIV-1-infected patients receiving HAART. Vaccination did not increase the risks of all-cause community-acquired pneumonia, HIV progression, and mortality. Vaccination did not increase PVL or decrease CD4+ among HIV-1-infected patients receiving HAART.     

Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: A randomised placebo-controlled study

The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4⁺ T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4⁺ and CD8⁺ T-cell responses, absolute CD4⁺ T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4⁺ T-cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (p < 0.05). Vaccine-induced HIV-1-specific CD4⁺ T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8⁺ T-cells or change in CD8⁺ T-cell activation marker expression profile was detected. Absolute CD4⁺ T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART-experienced subjects. In ART-naïve subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4⁺ T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4⁺ T-cell responses in ART-experienced and ART-naïve subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection.     

No changes on viral load and CD4+ T-cell counts following immunization with 7-valent pneumococcal conjugate vaccine among HIV-infected adults in Malawi

Vaccination has been associated with a transient increase in viremia in HIV-infected individuals, although contradicting evidence persist in the literature. As part of a randomized placebo-controlled efficacy trial of the PCV7 in Malawi, we collected viral load and CD4+ T-cell counts from 237 adults who received two doses of vaccine or placebo, administered 4 weeks apart. Analyses were conducted separately for cART and non-cART users. Our analysis show no difference in viral loads between vaccine and placebo groups, regardless of cART use. Viremia decreased from 4.1 to 2.9 log₁₀ copies/mL (p < 0.0001) among those using cART, consistent vaccine and placebo groups, but no changes were seen among the non-cART cohort. CD4+ T-cell counts remained unchanged regardless of cART use, or allocation to vaccine or placebo. We concluded that there was no evidence of detrimental effects of PCV7 administration on viral load or CD4+ T-cell counts six months after vaccination with PCV7.     

Phenotypic and functional characteristics of HIV-specific CD8 T cells and gag sequence variability after autologous dendritic cells based therapeutic vaccine

A decrease in HIV-1 specific CD8 T-cell responses associated with a partial control of viral replication occurred in 12 HIV-1-infected patients during autologous dendritic cells vaccination. HIV CD8 T cells were detected in 6/10 patients during immunizations, increasing after HAART discontinuation in 3 of them. Tet+ CD8 cells mainly had an effector phenotype (CD45RA−/+ CCR7− and CD28− and Perf+/−) and maintained IFN-γ release throughout follow-up. By contrast, patients with CD45RA−/+ CCR7+ Perf+ HIV-specific cells showed a decrease in peptide-specific IFN-γ production during vaccinations while levels were recovered when off HAART. No major mutations in either Gag p24 and p17 immunodominant epitopes were observed that might have explained the impaired CD8+ T-cell responses. Taken together, heterogeneity in the maturation status of HIV-specific CD8 T cells may be partially involved in the drop of peptide-specific IFN-γ production during immunizations.     

Safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine in HIV-1 infected former drug users

The immunogenicity of 23-valent pneumococcal polysaccharide vaccine was assessed in 57 HIV-1 infected former intravenous drug users and in 20 HIV-1 negative controls. The effect of vaccination on HIV-1 infection was studied in a subgroup of 38 patients, 60% of whom under highly active antiretroviral therapy (HAART). Antibody to capsular polysaccharides from Streptococcus pneumoniae serotypes 3, 4, 6B, 19F, 23 F, and changes in CD4+ count, HIV-1 RNA, proviral DNA and HIV-1 phenotype were measured in pre- and post-vaccination samples.Vaccinations were well-tolerated. The rate of responders was higher (P<0.05) in HIV-1 negative than in HIV-1 infected individuals. No difference in antibody response was found within HIV-1 infected patients stratified according to CD4+ counts. Post-vaccination antibody geometric mean concentrations (GMCs) to the five antigens were higher (P<0.05) than baseline in HIV-1 negative subjects, but not in HIV-1 positive individuals. Those with CD4+ >500 cells/mm(3) showed a significant increase of antibody against type 3 only. Immunisation caused no significant changes in CD4+ counts and in either plasma HIV-1 RNA nor proviral DNA levels. Pneumococcal vaccination does not induce virological or immunological deterioration in HIV infected patients, but the antibody response to a single dose of vaccine is poor.     

Soluble multi-trimeric TNF superfamily ligand adjuvants enhance immune responses to a HIV-1 Gag DNA vaccine

Background

DNA vaccines remain an important component of HIV vaccination strategies, typically as part of a prime/boost vaccination strategy with viral vector or protein boost. A number of DNA prime/viral vector boost vaccines are currently being evaluated for both preclinical studies and in Phase I and Phase II clinical trials. These vaccines would benefit from molecular adjuvants that increase correlates of immunity during the DNA prime. While HIV vaccine immune correlates are still not well defined, there are a number of immune assays that have been shown to correlate with protection from viral challenge including CD8+ T cell avidity, antigen-specific proliferation, and polyfunctional cytokine secretion.

Methodology and principal findings

Recombinant DNA vaccine adjuvants composed of a fusion between Surfactant Protein D (SP-D) and either CD40 Ligand (CD40L) or GITR Ligand (GITRL) were previously shown to enhance HIV-1 Gag DNA vaccines. Here we show that similar fusion constructs composed of the TNF superfamily ligands (TNFSFL) 4-1BBL, OX40L, RANKL, LIGHT, CD70, and BAFF can also enhanced immune responses to a HIV-1 Gag DNA vaccine. BALB/c mice were vaccinated intramuscularly with plasmids expressing secreted Gag and SP-D-TNFSFL fusions. Initially, mice were analyzed 2 weeks or 7 weeks following vaccination to evaluate the relative efficacy of each SP-D-TNFSFL construct. All SP-D-TNFSFL constructs enhanced at least one Gag-specific immune response compared to the parent vaccine. Importantly, the constructs SP-D-4-1BBL, SP-D-OX40L, and SP-D-LIGHT enhanced CD8+ T cell avidity and CD8+/CD4+ T cell proliferation 7 weeks post vaccination. These avidity and proliferation data suggest that 4-1BBL, OX40L, and LIGHT fusion constructs may be particularly effective as vaccine adjuvants. Constructs SP-D-OX40L, SP-D-LIGHT, and SP-D-BAFF enhanced Gag-specific IL-2 secretion in memory T cells, suggesting these adjuvants can increase the number of self-renewing Gag-specific CD8+ and/or CD4+ T cells. Finally adjuvants SP-D-OX40L and SP-D-CD70 increased T_H1 (IgG2a) but not T_H2 (IgG1) antibody responses in the vaccinated animals. Surprisingly, the B cell-activating protein BAFF did not enhance anti-Gag antibody responses when given as an SP-D fusion adjuvant, but nonetheless enhanced CD4+ and CD8+ T cell responses.

Conclusions

We present evidence that various SP-D-TNFSFL fusion constructs can enhance immune responses following DNA vaccination with HIV-1 Gag expression plasmid. These data support the continued evaluation of SP-D-TNFSFL fusion proteins as molecular adjuvants for DNA and/or viral vector vaccines. Constructs of particular interest included SP-D-OX40L, SP-D-4-1BBL, SP-D-LIGHT, and SP-D-CD70. SP-D-BAFF was surprisingly effective at enhancing T cell responses, despite its inability to enhance anti-Gag antibody secretion.     

Quadrivalent HPV vaccine in HIV-1-infected early adolescent girls and boys in Kenya: Month 7 and 12 post vaccine immunogenicity and correlation with immune status

IntroductionIn sub-Saharan Africa, a generation of HIV-1-infected children is approaching the age of sexual debut and becoming at risk for HPV infection and its sequelae. We assessed safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in HIV-1-infected adolescents.MethodsIn an open-label trial among Kenyan, HIV-1-infected adolescents aged 9–14 years, we administered the qHPV vaccine at 0, 2 and 6 months and measured antibody titers to HPV-16, 18, 6 and 11 at month 7 and 12 post-vaccination. Measures of immunogenic response from HIV-1-negative historical cohorts from Africa and HIV-1 positive adolescent cohorts from the USA were used for comparison.ResultsWe enrolled 100 girls and 80 boys with a median age of 12 years and median baseline CD4 cell count of 684 (IQR 478, 935) cells/µL. One hundred and fifty four (86%) were receiving antiretroviral therapy for a median of 4.5 (IQR 2.3, 6.3) years; 110 (71%) had <400 copies of plasma HIV-1 RNA/mL. Of 189 enrolled children, 179 received all three doses. Two hundred and eighty five (64%) of 445 adverse events were injection site reactions; none were greater than grade 2. Of 6 Serious Adverse Events (SAEs), none were considered vaccine related. Seroconversion to HPV-18, 16, 11, 6 at month 7 occurred in 93.3%, 98.3%, 97.2% and 99.6% of vaccine recipients; similar rates have been reported in historical controls. The mean log₁₀ HPV antibody titer measured at month 7 increased with each log₁₀ increase in CD4 by 1.4 (95% CI: 1.1–1.7) for HPV-18; 1.2 (0.9–1.4) for HPV-16; 1.1 (0.8–1.3) for HPV-11; 0.7 (0.5–1.0) for HPV-6 (all p < 0.0001).ConclusionAlmost all Kenyan HIV-1-infected adolescents mounted an immune response comparable to other immunized populations. HPV antibody titers were higher in those with preserved CD4 cell counts. Longer term-follow up will determine sustainability of the immune response.ClinicalTrials.gov number, NCT00557245.     

The safety and immunogenicity of an adenovirus type 35-vectored TB vaccine in HIV-infected,BCG-vaccinated adults with CD4+ T cell counts >350 cells/mm3

BackgroundThe safety and immunogenicity of a replication deficient adenovirus serotype 35 tuberculosis (TB) vaccine containing gene inserts for Antigens (Ag) 85A, Ag85B and TB10.4 (AERAS-402/AD35.TB-S) was evaluated in previously BCG vaccinated, HIV-infected South African adults with baseline CD4 counts >350 cells/mm³.MethodsSubjects were randomized (1:1) to receive two doses of either intramuscular AERAS-402/AD35.TB-S or placebo at month 0 and at month 1. Participants were monitored for adverse events 28 days after each vaccination and for serious adverse events over 12 months. CD4⁺ and CD8⁺ T-cell and antibody responses to vaccine antigens were evaluated post first and second vaccination.Results26 subjects were randomly assigned to receive AERAS-402/AD35.TB-S (N = 13) or placebo (N = 13). The mean age was 29.0 years, all were Black-African, 88.5% were female, 46.2% were QuantiFERON Test (QFT) positive at baseline, and the median CD4 count was 559.5 cells/mm³, all similar by treatment group. All subjects received their first vaccination and 24 subjects received their second vaccination. Injection site reactions and some systemic reactions were reported more commonly in the AERAS-402/AD35.TB-S versus placebo recipients. AERAS-402/AD35.TB-S did not appear to influence CD4 counts and HIV-1 viral load over the course of study follow-up. AERAS-402/AD35.TB-S induced a mixed CD4⁺ T-cell and CD8⁺ T-cell responses to Ag85B. The CD4⁺ T-cell responses peaked to Ag85A and Ag85B 14 days after the second vaccination and had declined by Day 182. AERAS-402/AD35.TB-S predominantly induced CD4⁺ T-cells expressing three (IFN-γ, TNF, IL-2) or two (IL-2 and TNF) cytokines, two weeks after the last vaccination, which did not differ by baseline Quantiferon test status. AERAS-402/AD35.TB-S induced strong Ag85A and Ag85B specific antibody responses, particularly after the second vaccination.ConclusionAERAS-402/AD35.TB-S was well tolerated, safe and induced predominantly polyfunctional CD4⁺ and CD8⁺ T-cell responses to vaccine.     

Immunogenicity and tolerability of an inactivated and adjuvanted pandemic H1N1 influenza vaccine, in HIV-1-infected patients

We evaluated the efficacy and tolerability of a single dose of the split virion AS03-adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in 84 HIV-1 infected individuals. Antibody titers were determined by hemagglutination inhibition assay and by microneutralization. Vaccine was well tolerated. At 21 days post vaccination, 56 (67%) patients had seroconverted. There was no correlation between baseline CD4 cell count (p = 0.539) or HIV viral load (p = 0.381) and immune response. Other vaccine strategies should be evaluated in this HIV population, to improve response rates.     

Induction of opsonophagocytic killing activity with pneumococcal conjugate vaccine in human immunodeficiency virus-infected Ugandan adults

The levels of IgG determined by ELISA may have limited relevance in human immunodeficiency virus (HIV)-infected adults because of non-functional antibodies. 58 HIV-1-infected and 29 HIV-uninfected Ugandan adults were immunized with conjugate vaccine (CV) followed by polysaccharide vaccine (PV) after a 2-month interval, and the opsonophagocytic killing (OPK) titers against serotype 4 or 14 pneumococcal strains as well as the levels of serotype-specific IgG in sera were determined. Significant increases were found in the OPK titers and IgG levels for both serotypes after CV vaccination irrespective of HIV status. Increases in IgG levels and OPK titers were largely dependent on the CD4(+) cell counts, except for increases in the IgG levels for serotype 4. The proportions with serum OPK titer equal to or greater than 8 were 0-4.3% for serotype 4 and 26.7-42.9% for serotype 14 before vaccination, but the proportions increased up to 43.3-86.2% for serotype 4 and 63.3-96.6% for serotype 14 in all three groups 2 months after CV vaccination. The serum OPK titers remained at levels higher than the pre-vaccination level for at least 8 months after CV vaccination. A single dose of CV could afford some protective immunity in HIV-infected African adults before the introduction of antiretroviral therapy.     

Live vaccinia-rabies virus recombinants, but not an inactivated rabies virus cell culture vaccine, protect B-lymphocyte-deficient A/WySnJ mice against rabies: considerations of recombinant defective poxviruses for rabies immunization of immunocompromised individuals

Presently, commercially available cell culture rabies vaccines for humans and animals consist of the five inactivated rabies virus proteins. The vaccines elicit a CD4+ helper T-cell response and a humoral B-cell response against the viral glycoprotein (G) resulting in the production of virus neutralizing antibody. Antibody against the viral nucleoprotein (N) is also present, but the mechanism(s) of its protection is unclear. HIV-infected individuals with low CD4+ T-lymphocyte counts and individuals undergoing treatment with immunosuppressive drugs have an impaired neutralizing antibody response after pre- and post-exposure immunization with rabies cell culture vaccines. Here we show the efficacy of live vaccinia-rabies virus recombinants, but not a cell culture vaccine consisting of inactivated rabies virus, to elicit elevated levels of neutralizing antibody in B-lymphocyte deficient A/WySnJ mice. The cell culture vaccine also failed to protect the mice, whereas a single immunization of a vaccinia recombinant expressing the rabies virus G or co-expressing G and N equally protected the mice up to 18 months after vaccination. The data suggest that recombinant poxviruses expressing the rabies virus G, in particular replication defective poxviruses such as canarypox or MVA vaccinia virus that undergo abortive replication in non-avian cells, or the attenuated vaccinia virus NYVAC, should be evaluated as rabies vaccines in immunocompromised individuals.     

Vaccination against hepatitis B with 4-double doses increases response rates and antibodies titers in HIV-infected adults

BackgroundAntibody responses to standard regimens of hepatitis B (HBV) vaccination are lower in HIV-infected subjects and the best hepatitis B vaccine schedule in this population is not known.ObjectiveTo assess the immunogenicity and to evaluate predictors of serologic response of a modified regimen of a HBV recombinant vaccine in a cohort of HIV-infected subjects.MethodsHIV-infected subjects received 4 doses (40 μg) of a recombinant HBV vaccine at 0, 1, 2 and 6 months. Demographic information as well as CD4 cell count and plasma viral load were assessed at baseline. Protective and strong responses were defined as an anti-HBs titer ≥10 mIU/mL and ≥100 mIU/mL, respectively and were evaluated one month after the third and the fourth doses.Results163 HIV-infected individuals were evaluated 67 (40%) were male and median age was 37 years. Median CD4 cell count was 385 cells/mm³ and 113 (70%) had undetectable HIV-1 viral load. Protective antibody response was observed in 83 and 91% and a strong antibody response was observed in 62 and 80% of the subjects after 3 and 4 doses, respectively.In a multivariate logistic model undetectable HIV-1 viral load and higher CD4 cell counts were independent predictors of a strong antibody response after 4 doses. Patients with undetectable HIV viral load were almost 3 times more likely to have anti-HBs titers above 100 mIU/mL than those with detectable viral load.ConclusionsA 4-double-dose regimen of a recombinant HBV vaccine increased response rates and determined higher antibody titers which may translate in prolonged protection agains HBV. Inclusion of a fourth dose of HBV vaccine for HIV-infected subjects should be considered in the public health setting.     

Randomised trial of intradermal Mycobacterium vaccae or intradermal hepatitis B immunisation in children with HIV infection.

This study assessed the safety of inactivated Mycobacterium vaccae as a candidate vaccine to prevent disseminated mycobacterial disease in children with HIV infection. 35 children ages 1-8 with CD4 counts > or =300/mm3 in New Hampshire, Boston and Chicago were randomised in a 2:1 schedule to receive a 3-dose series of intradermal M. vaccae vaccine (MV) or hepatitis B vaccine (HBV) at 2-month intervals. Immunisation was safe and well tolerated; 2-day median vaccine site in duration was 5 mm in MV recipients and 0 mm in HBV recipients (p < 0.001). There were no significantly different changes in viral load or CD4 count between the two vaccine groups. No PPD skin test conversions occurred after immunisation. MV is safe and well tolerated and deserves further evaluation as a vaccine to prevent mycobacterial disease in HIV-infected children.     

国产液体无佐剂狂犬病疫苗免疫应答动态观察

目的评价国产液体无佐剂非洲绿猴肾(Vero)细胞狂犬病疫苗的免疫原性。方法 选择既往无明确狂犬病疫苗接种史和犬伤史,符合研究方案制定的入选标准和排除标准,对暴露于狂犬病患者采用常规5针注射。观察对象于首针接种前,首针接种后7、14、28、45 d,全程后180 d采集血样检测抗狂犬病中和抗体。结果符合入选标准和排除标准的观察对象120名常规接种5针液体无佐剂Vero细胞狂犬病疫苗。观察对象接种前狂犬病抗体均为阴性,接种首针后7 d狂犬病抗体阳转率为10.83%,接种首针后14 d阳转率达到100%,接种首针后28 d、45 d和全程后6个月的阳性率均为100%。接种首针后7 d狂犬病抗体几何平均滴度(GMT)仅为0.08 IU/ml,接种首针后14 d狂犬病抗体的GMT达到1.02 IU/ml,较首针接种后7 d增长12.75倍。接种首针后28、45 d狂犬病抗体的GMT分别达到4.93 IU/ml、9.71 IU/ml,较首针后14 d分别增长4.83倍、9.52倍。全程接种后6个月狂犬病抗体的GMT仍达到6.25 IU/ml。结论国产液体无佐剂Vero细胞狂犬病疫苗具有良好的免疫原性,6个月内再被暴露于狂犬病动物者可以不需要接种狂犬病疫苗。