Heterologous cAd3-Ebola and MVA-EbolaZ vaccines are safe and immunogenic in US and Uganda phase 1/1b trials.

Ebola virus disease (EVD) is a filoviral infection caused by virus species of the Ebolavirus genus including Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV). We investigated the safety and immunogenicity of a heterologous prime-boost regimen involving a chimpanzee adenovirus 3 vectored Ebola vaccine [either monovalent (cAd3-EBOZ) or bivalent (cAd3-EBO)] prime followed by a recombinant modified vaccinia virus Ankara EBOV vaccine (MVA-EbolaZ) boost in two phase 1/1b randomized open-label clinical trials in healthy adults in the United States (US) and Uganda (UG). Trial US (NCT02408913) enrolled 140 participants, including 26 EVD vaccine-naïve and 114 cAd3-Ebola-experienced participants (April-November 2015). Trial UG (NCT02354404) enrolled 90 participants, including 60 EVD vaccine-naïve and 30 DNA Ebola vaccine-experienced participants (February-April 2015). All tested vaccines and regimens were safe and well tolerated with no serious adverse events reported related to study products. Solicited local and systemic reactogenicity was mostly mild to moderate in severity. The heterologous prime-boost regimen was immunogenic, including induction of durable antibody responses which peaked as early as two weeks and persisted up to one year after each vaccination. Different prime-boost intervals impacted the magnitude of humoral and cellular immune responses. The results from these studies demonstrate promising implications for use of these vaccines in both prophylactic and outbreak settings.

Associations Between Antibody Fc-Mediated Effector Functions and Long-Term Sequelae in Ebola Virus Survivors.

Antibodies that mediate non-neutralizing functions play an important role in the immune response to Ebola virus (EBOV) and are thought to impact disease outcome. EBOV has also been associated with long term sequelae in survivors, however, the extent to which antibodies that mediate non-neutralizing functions are associated with the development of these sequelae is unknown. Here, the presence of antibodies mediating different effector functions and how they relate to long-term sequelae two years after the 2007 Bundibugyo Ebola virus (BDBV) outbreak was investigated. The majority of survivors demonstrated robust antibody effector functional activity and demonstrated persistent polyfunctional antibody profiles to the EBOV glycoprotein (GP) two years after infection. These functions were strongly associated with the levels of GP-specific IgG1. The odds of developing hearing loss, one of the more common sequelae to BDBV was reduced when antibodies mediating antibody dependent cellular phagocytosis (ADCP), antibody dependent complement deposition (ADCD), or activating NK cells (ADNKA) were observed. In addition, hearing loss was associated with increased levels of several pro-inflammatory cytokines and levels of these pro-inflammatory cytokines were associated with lower ADCP. These results are indicating that a skewed antibody profile and persistent inflammation may contribute to long term outcome in survivors of BDBV infection.

Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study.

BACKGROUND: The limited data available for long-term Ebola virus disease health outcomes suggest that sequelae persist for longer than 1 year after infection. The magnitude of the present outbreak in west Africa necessitates a more complete understanding of the health effects and future medical needs of these patients. METHODS: We invited adult survivors of the 2007 Bundibugyo Ebola virus outbreak in Uganda and their contacts to take part in an observational study roughly 29 months after the outbreak. We collected information about health status, functional limitations, and demographics. We collected blood samples for clinical chemistry, haematology, and filovirus antibodies using ELISA. Analyses were restricted to probable and confirmed survivors and their seronegative contacts. FINDINGS: We recruited 70 survivors of the 2007 Bundibugyo Ebola virus and 223 contacts. We did analyses for 49 probable and confirmed survivors and 157 seronegative contacts. Survivors of the Bundibugyo Ebola virus were at significantly increased risk of ocular deficits (retro-orbital pain [RR 4·3, 95% CI 1·9-9·6; p<0·0001], blurred vision [1·9, 1·1-3·2; p=0·018]), hearing loss (2·3, 1·2-4·5; p=0·010), difficulty swallowing (2·1, 1·1-3·9; p=0·017), difficulty sleeping (1·9, 1·3-2·8; p=0·001), arthralgias (2·0, 1·1-3·6; p=0·020), and various constitutional symptoms controlling for age and sex. Chronic health problems (prevalence ratio [PR] 2·1, 95% CI 1·2-3·6; p=0·008) and limitations due to memory loss or confusion (PR 5·8, 1·5-22·4; p=0·010) were also reported more frequently by survivors of Bundibugyo Ebola virus. INTERPRETATION: Long-term sequelae persist for more than 2 years after Ebola virus disease. Definition of health consequences related to Ebola virus disease could improve patient care for survivors and contribute to understanding of disease pathogenesis. FUNDING: Chemical Biological Technologies Directorate, Defense Threat Reduction Agency.

Short communication: east meets west: a description of HIV-1 drug resistance mutation patterns of patients failing first line therapy in PEPFAR clinics from Uganda and Nigeria.

HIV-1 viral load (VL) monitoring is recommended but seldom performed in resource-constrained countries. An evaluation of patients receiving first-line antiretroviral therapy in a multicountry PEPFAR program (RV288) was performed to determine the rates and predictors of virologic suppression. Resistance data from treatment failures are available from Uganda and Nigeria. Each country enrolled 325 subjects into this cross-sectional study. Subjects on first-line therapy were randomly selected for HIV RNA testing (viral load). Regimens included efavirenz or nevirapine with zidovudine/lamivudine or tenofovir/lamivudine. VL was determined from plasma using the Roche COBAS TaqMan HIV-1 Test, High Pure System v1.0 (47 copies/ml). Genotypic resistance testing was performed on samples with VL>1,000 copies/ml. From Uganda, 85% of subjects were undetectable while 7% (23/325) had VL>1,000 copies/ml. The HIV-1 subtype distribution was as follows: A=47.6%, C=14.3%, and D=38.1%. No resistance mutations were found in 14% of subjects. All subjects with resistance had the M184V mutation. Of subjects failing a zidovudine regimen less than 1 year, 88% (7/8) had no thymidine analogue mutations (TAMs), compared to 50% (4/8) failing greater than 1 year. Four subjects (25%) had more than two mutations from the TAM-1 pathway (41L, 210W, 215Y). In Nigeria, 82% were undetectable while 14% (45/325) had VL>1,000 copies/ml. HIV-1 subtype distribution was as follows: 62.8%=CRF02_AG, 34%=pure G, and 2.8%=A. Of the 35 genotyped subjects, 14% (5/35) had no resistance mutations. Of the remainder, 10% (3/30) had no nucleoside analogue mutations while 33% (10/30) had only M184V along with nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations. Forty percent (10/25) of subjects on zidovudine failed without TAMs. Another 25% (5/25) of subjects failing on zidovudine had more than two TAM-1 mutations. Individuals failing first-line antiretroviral therapy (ART) may retain sensitivity to one or more nucleoside analogues from the regimen. Knowledge of drug resistance patterns allow for selection of drugs that can be recycled in future regimens. Accumulation of resistance mutations may compromise future treatment options.