Adjuvantation of a SARS-CoV-2 mRNA vaccine with controlled tissue-specific expression of an mRNA encoding IL-12p70.

Messenger RNA (mRNA) vaccines were pivotal in reducing severe acute respiratory syndrome 2 (SARS-CoV-2) infection burden, yet they have not demonstrated robust durability, especially in older adults. Here, we describe a molecular adjuvant comprising a lipid nanoparticle (LNP)-encapsulated mRNA encoding interleukin-12p70 (IL-12p70). The bioactive adjuvant was engineered with a multiorgan protection (MOP) sequence to restrict transcript expression to the intramuscular injection site. Admixing IL-12-MOP (CTX-1796) with the BNT162b2 SARS-CoV-2 vaccine increased spike protein-specific immune responses in mice. Specifically, the benefits of IL-12-MOP adjuvantation included amplified humoral and cellular immunity and increased immune durability for 1 year after vaccination in mice. An additional benefit included the restoration of immunity in aged mice to amounts comparable to those achieved in young adult animals, alongside amplification with a single immunization. Associated enhanced dendritic cell and germinal center responses were observed. Together, these data demonstrate that an LNP-encapsulated IL-12-MOP mRNA-encoded adjuvant can amplify immunogenicity independent of age, demonstrating translational potential to benefit vulnerable populations.

Protective effect of IgM against colonization of the respiratory tract by nontypeable Haemophilus influenzae in patients with hypogammaglobulinemia.

BACKGROUND: Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not known whether patients able to secrete IgM (eg, those with hyper-IgM [HIgM] syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia [PHG]). OBJECTIVE: This study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome. METHODS: A cohort of patients with HIgM syndrome (n = 25) and a cohort of patients with PHG (n = 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured. RESULTS: When compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti-nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections. CONCLUSIONS: IgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.

Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. OBJECTIVE: We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. METHODS: We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. RESULTS: Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. CONCLUSION: Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies.

Elevated IL-6/IL-1Ra ratio as a prognostic biomarker of poor chemotherapy efficacy in Chinese patients with metastatic NSCLC, validated in a Caucasian patient cohort.

The treatment options for advanced (stage IV) non-small cell lung cancer (NSCLC) at diagnosis remain disappointing. The development of immunotherapeutic drugs may represent a promising alternative approach to the treatment of late-stage cancer at diagnosis. These current paradigms in cancer treatment highlight the need for new biomarkers related to the immune status of the patients and/or the tumor microenvironment, for immune as well as chemotherapeutic treatment options. The aim of the present study was to analyze soluble immune factors in patients with lung cancer treated with chemotherapy to identify prognostic biomarkers. For this purpose, the data obtained from two cohorts of patients from different clinical trials were analyzed: A Chinese patient cohort to identify potential prognostic biomarkers, and a validation cohort comprising patients with a similar clinical stage from a clinical trial in Europe. Analyses of soluble markers for inflammation and immune status were performed by standard assays and multiplex Luminex assays. Differences in overall survival (OS) and progression-free survival (PFS) were evaluated with the log-rank test and robustness was evaluated with the resampling approach. In the Chinese cohort, four prognostic biomarkers of poor response to chemotherapy were identified, which had a significant impact on OS and PFS. It was confirmed in the Caucasian validation cohort that an increased value of the interleukin (IL)-6/IL-1Ra cytokine ratio at inclusion was correlated with significantly shorter OS and PFS, whereas no other biomarkers were found to be significant. The IL-6/IL-1Ra ratio reflects the imbalance between pro- and anti-inflammatory status in the plasma of patients and may be associated with tumor inflammatory status and the therapeutic outcome. The present study highlights the identification of the IL-6/IL-1Ra ratio as a biomarker of poor prognosis in terms of response to chemotherapy in two independent clinical studies.

Typing of killer-cell immunoglobulin-like receptors and their cognate human leukocyte antigen class I ligands predicts survival of Chinese Han patients with metastatic non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) may establish an immunosuppressive tumor microenvironment that is conducive to tumor growth. Natural killer (NK) cells play a pivotal role in immunological surveillance. Activation of NK cells partially depends on the interactions between killer-cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. We herein investigated the association of KIRs and HLA ligands with survival in metastatic NSCLC (mNSCLC) patients treated with chemotherapy in a Chinese Han population. Polymerase chain reaction with sequence-specific primers was used to type 15 KIRs at the DNA and mRNA level and 6 HLA ligands in 70 mNSCLC patients. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard regression model was applied for multivariate survival analysis, with the stepwise selection, to determine independent predictors of survival. It was observed that patients with KIR2DS4del gene expression at the mRNA level or HLA-Bw4T80 exhibited poor overall survival (OS). The multivariate analysis revealed that HLA-Bw4T80 and KIR2DS4del expression were independent predictors of OS. This observation indicated that the KIR/HLA ligand is a promising predictor of survival in mNSCLC and may also provide a strategy for treatment stratification and patient management.

[Viral encephalitis virus, a new bioterrorist menace]. / Les virus des encéphalites virales, une nouvelle menace bioterroriste.

Often responsible for little known infections, today viral encephalitis viruses appear as a new bioterrorist menace, because of their easy production and their great pathogenic potential. Spraying is the best way to permit the rapid diffusion of certain encephalitis viruses. Diagnosis of viral encephalitis, predominating in tropical surroundings, is difficult. In the majority of cases, symptoms differ little from those of common flu. With supplementary examinations, the biological abnormalities are usually non-specific. There are no characteristic images on scans or MRI. Identification of the virus in the nasopharynx, blood or cerebrospinal fluid, in serology, PCR or RT-PCR permits confirmation of the virus. Treatment is essentially symptomatic and relies on appropriate reanimation measures. Ribavirin can be indicated in some cases such as the Rift Valley fever, but is formally contraindicated in West Nile encephalitis. The aim of terrorist groups who would use this type of weapon is more to provoke panic and disorganisation than to kill as many people as possible.

Cost-effectiveness of primary prophylaxis of AIDS associated cryptococcosis in Cambodia.

BACKGROUND: Cryptococcal infection is a frequent cause of mortality in Cambodian HIV-infected patients with CD4+ count ≤100 cells/µl. This study assessed the cost-effectiveness of three strategies for cryptococcosis prevention in HIV-infected patients. METHODS: A MARKOV DECISION TREE WAS USED TO COMPARE THE FOLLOWING STRATEGIES AT THE TIME OF HIV DIAGNOSIS: no intervention, one time systematic serum cryptococcal antigen (CRAG) screening and treatment of positive patients, and systematic primary prophylaxis with fluconazole. The trajectory of a hypothetical cohort of HIV-infected patients with CD4+ count ≤100 cells/µl initiating care was simulated over a 1-year period (cotrimoxazole initiation at enrollment; antiretroviral therapy within 3 months). Natural history and cost data (US$ 2009) were from Cambodia. Efficacy data were from international literature. RESULTS: In a population in which 81% of patients had a CD4+ count ≤50 cells/ µl and 19% a CD4+ count between 51-100 cells/µl, the proportion alive 1 year after enrollment was 61% (cost $ 472) with no intervention, 70% (cost $ 483) with screening, and 72% (cost $ 492) with prophylaxis. After one year of follow-up, the cost-effectiveness of screening vs. no intervention was US$ 180/life year gained (LYG). The cost-effectiveness of prophylaxis vs. screening was $ 511/LYG. The cost-effectiveness of prophylaxis vs. screening was estimated at $1538/LYG if the proportion of patients with CD4+ count ≤50 cells/µl decreased by 75%. CONCLUSION: In a high endemic area of cryptococcosis and HIV infection, serum CRAG screening and prophylaxis are two cost effective strategies to prevent AIDS associated cryptococcosis in patients with CD4+ count ≤100 cells/µl, at a short-term horizon, screening being more cost-effective but less effective than prophylaxis. Systematic primary prophylaxis may be preferred in patients with CD4+ below 50 cells/µl while systematic serum CRAG screening for early targeted treatment may be preferred in patients with CD4+ between 51-100 cells/µl.

Prevalence, risk factors, and impact on outcome of cytomegalovirus replication in serum of Cambodian HIV-infected patients (2004-2007).

BACKGROUND: In developing countries, the study of cytomegalovirus (CMV) coinfection in HIV-infected patients remains neglected. Quantitative CMV polymerase chain reaction (PCR) is the gold standard diagnostic tool for analyzing serum CMV replication and for predicting CMV disease. We estimated the prevalence of replicating CMV in sera of newly diagnosed HIV-infected Cambodian patients and examined its impact on mortality. METHODS: This cohort study was based on 2 highly active antiretroviral therapy treatment programs in Cambodia between 2004 and 2007. Quantitative CMV PCR was performed on baseline serum samples of 377 HIV-infected patients. RESULTS: The prevalence of serum CMV DNA was 55.2% (150 of 272) in patients with CD4 count <100/mm. In multivariate analysis, hemoglobin <9 g/dL, CD4 count <100/mm, and Karnofsky index <50 were independently associated with positive serum CMV DNA at baseline. During a 3-year follow-up period, CMV viral load >or=3.1 log10 copies per milliliter was significantly associated with death independently of CD4 count, other opportunistic infections, and highly active antiretroviral therapy. CONCLUSIONS: As in industrialized countries, serum CMV replication is highly prevalent among HIV-infected Cambodian patients and is associated with increased mortality. This underscores the importance of diagnostic CMV infection by PCR in sera of HIV-infected patients with CD4 count <100/mm and treating this opportunistic infection to reduce its associated mortality.

Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients.

OBJECTIVES: To determine the prevalence, determinants ofpositivity, and clinical utility of serum cryptococcal polysaccharide (CPS) antigen testing among HIV-infected patients in 2004 in Cambodia, an area highly endemic for cryptococcosis. METHODS: All HIV-infected patients with a CD4+ count <200 cells/mm3 attending 1 of 2 Phnom Penh hospitals for the first time were systematically screened for serum CPS. Patients with positive test results were further investigated to identify those with cryptococcal meningitis (CM), pulmonary cryptococcosis, or isolated positive cryptococcal antigenemia (IPCA). RESULTS: The median (interquartile range [IQR]) CD4+ count of 327 enrolled patients was 24 (IQR: 8 to 65) cells/mm3. The prevalence of cryptococcal infection was 59 (18.0%) of 327 cases, of which 41 were CM and 10 were IPCA. In the absence of serum CPS detection, 17 (28.8%) of 59 cryptococcal infections would have been missed on the day of consultation. In patients with no specific symptoms of meningoencephalitis, the prevalence of positive serum CPS detection was 32 (10.8%) of 295 cases. Countryside residence (adjusted odds ratio [AOR] = 3.6), headache (AOR = 3.2), body mass index <15.4 kg/m2 (AOR = 3.4), CD4+ count <50 cells/mm3 (AOR = 4.0), and male gender (marginally, AOR = 2.1) were all independently associated with a positive test results. CONCLUSION: Serum CPS screening among AIDS patients with a CD4+ count <100 cells/mm3 is useful in areas highly endemic for cryptococcosis, allowing early diagnosis and treatment of this opportunistic infection.