Infectious Disease

Appiah, G. D., J. R. Chung, B. Flannery, F. Havers, R. K. Zimmerman, M. P. Nowalk, A. S. Monto, E. T. Martin, M. Gaglani, K. Murthy, L. A. Jackson, M. L. Jackson, H. Q. McLean, E. A. Belongia and A. M. Fry (2018). “Hospitalization following Outpatient Medical Care for Influenza: US Influenza Vaccine Effectiveness Network, 2011-12-2015-16.” Influenza Other Respir Viruses Nov 8. [Epub ahead of print].

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Over five seasons, we determined the proportion of outpatients with laboratory-confirmed, influenza-associated illness who were hospitalized within 30 days following the outpatient visit. Overall, 136 (1.7%) of 7,813 influenza-positive patients were hospitalized a median of 4 days after an outpatient visit. Patients aged >/=65 years and those with high-risk conditions were at increased risk of hospitalization. After controlling for age and high-risk conditions, vaccination status and infecting influenza virus type were not associated with hospitalization risk among adults.

Magombedze, G., N. M. Ferguson and A. C. Ghani (2018). “A trade-off between dry season survival longevity and wet season high net reproduction can explain the persistence of Anopheles mosquitoes.” Parasit Vectors Nov 3;11(1):576.

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BACKGROUND: Plasmodium falciparum malaria remains a leading cause of death in tropical regions of the world. Despite efforts to reduce transmission, rebounds associated with the persistence of malaria vectors have remained a major impediment to local elimination. One area that remains poorly understood is how Anopheles populations survive long dry seasons to re-emerge following the onset of the rains. METHODS: We developed a suite of mathematical models to explore the impact of different dry-season mosquito survival strategies on the dynamics of vector populations. We fitted these models to an Anopheles population data set from Mali to estimate the model parameters and evaluate whether incorporating aestivation improved the fit of the model to the observed seasonal dynamics. We used the fitted models to explore the impact of intervention strategies that target aestivating mosquitoes in addition to targeting active mosquitoes and larvae. RESULTS: Including aestivation in the model significantly improved our ability to reproduce the observed seasonal dynamics of vector populations as judged by the deviance information criterion (DIC). Furthermore, such a model resulted in more biologically plausible active mosquito survival times (for A. coluzzii median wet season survival time of 10.9 days, 95% credible interval (CrI): 10.0-14.5 days in a model with aestivation versus 38.1 days, 95% CrI: 35.8-42.5 days in a model without aestivation; similar patterns were observed for A. arabiensis). Aestivation also generated enhanced persistence of the vector population over a wider range of both survival times and fecundity levels. Adding vector control interventions that target the aestivating mosquito population is shown to have the potential to enhance the impact of existing vector control. CONCLUSIONS: Dry season survival attributes appear to drive vector population persistence and therefore have implications for vector control. Further research is therefore needed to better understand these mechanisms and to evaluate the additional benefit of vector control strategies that specifically target dormant mosquitoes.

Havers, F. P., J. R. Chung, E. A. Belongia, H. Q. McLean, M. Gaglani, K. Murthy, R. K. Zimmerman, M. P. Nowalk, M. L. Jackson, L. A. Jackson, A. S. Monto, J. G. Petrie, A. M. Fry and B. Flannery (2018). “Influenza Vaccine Effectiveness and Statin Use Among Adults in the United States, 2011-2017.” Clin Infect Dis Oct 27. [Epub ahead of print].

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Background: Statin medications have immunomodulatory effects. Several recent studies suggest that statins may reduce influenza vaccine response and reduce influenza vaccine effectiveness (VE). Methods: We compared influenza VE in statin users and nonusers aged >/=45 years enrolled in the US Vaccine Effectiveness Network study over 6 influenza seasons (2011-2012 through 2016-2017). All enrollees presented to outpatients clinics with acute respiratory illness and were tested for influenza. Information on vaccination status, medical history, and statin use at the time of vaccination were collected by medical and pharmacy records. Using a test-negative design, we estimated VE as (1 – OR) x 100, in which OR is the odds ratio for testing positive for influenza virus among vaccinated vs unvaccinated participants. Results: Among 11692 eligible participants, 3359 (30%) were statin users and 2806 (24%) tested positive for influenza virus infection; 78% of statin users and 60% of nonusers had received influenza vaccine. After adjusting for potential confounders, influenza VE was 36% (95% confidence interval [CI], 22%-47%) among statin users and 39% (95% CI, 32%-45%) among nonusers. We observed no significant modification of VE by statin use. VE against influenza A(H1N1)pdm09, A(H3N2), and B viruses were similar among statin users and nonusers. Conclusions: In this large observational study, influenza VE against laboratory-confirmed influenza illness was not affected by current statin use among persons aged >/=45 years. Statin use did not modify the effect of vaccination on influenza when analyzed by type and subtype.

Flannery, B., J. R. Chung, A. S. Monto, E. T. Martin, E. A. Belongia, H. Q. McLean, M. Gaglani, K. Murthy, R. K. Zimmerman, M. P. Nowalk, M. L. Jackson, L. A. Jackson, M. A. Rolfes, S. Spencer and A. M. Fry (2018). “Influenza Vaccine Effectiveness in the United States during the 2016-2017 Season.” Clin Infect Dis Sep 11. [Epub ahead of print].

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Background: In recent influenza seasons, the effectiveness of inactivated influenza vaccines against circulating A(H3N2) virus has been lower than against A(H1N1)pdm09 and B viruses, even when circulating viruses remained antigenically similar to vaccine components. Methods: During the 2016-2017 influenza season, vaccine effectiveness (VE) across age groups and vaccine types was examined among outpatients with acute respiratory illness at 5 US sites using a test-negative design that compared the odds of vaccination among reverse transcription polymerase chain reaction-confirmed influenza positives and negatives. Results: Among 7083 enrollees, 1342 (19%) tested positive for influenza A(H3N2), 648 (9%) were positive for influenza B (including B/Yamagata, n = 577) and 5040(71%) were influenza negative. Vaccine effectiveness was 40% (95% confidence interval [CI], 32% to 46%) against any influenza virus, 33% (95%CI, 23% to 41%) against influenza A(H3N2) viruses and 53% (95%CI, 43% to 61%) against influenza B viruses. Conclusions: The 2016-2017 influenza vaccines provided moderate protection against any influenza among outpatients, but were less protective against influenza A(H3N2) viruses than B viruses. Approaches to improving effectiveness against A(H3N2) viruses are needed.

Cheng, L., Q. Wang, G. Li, R. Banga, J. Ma, H. Yu, F. Yasui, Z. Zhang, G. Pantaleo, M. Perreau, S. Zurawski, G. Zurawski, Y. Levy and L. Su (2018). “TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs.” J Clin Invest 128(10): 4387-4396.

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Activation of HIV-1 reservoirs and induction of anti-HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4+ and CD8+ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (alphaCD40.HIV5pep). We show that alphaCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1-specific human CD8+ and CD4+ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1-infected hu-mice under effective cART, alphaCD40.HIV5pep with poly(I:C) vaccination induced HIV-1-specific CD8+ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the alphaCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti-HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti-HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.