Bio

Bio


Dr. Vu is a pediatric infectious diseases specialist who is researching human responses to dengue virus and malaria infections. He performed his undergraduate studies at the University of California, San Diego, and obtained his medical doctorate at the University of Pennsylvania School of Medicine. He trained in general pediatrics at UCSF Benioff Children's Hospital Oakland, and in pediatric infectious diseases at Emory University School of Medicine. His present studies on pediatric dengue and malaria co-infection are supported by an NIAID Career Development Award (K23 AI127909) and a Instructor K Award Support Program Award from the Maternal & Child Health Research Institute and Department of Pediatrics.

Clinical Focus


  • Pediatric Infectious Diseases

Honors & Awards


  • KL-2 Career Development Award, Spectrum (Stanford CTSA) (7/2016-6/2018)
  • Ruth L. Kirschstein National Research Service Award, NIAID, NIH (7/2003-6/2006)

Professional Education


  • Residency:UCSF Pediatric Fellowships (2002) CA
  • Board Certification: Pediatric Infectious Diseases, American Board of Pediatrics (2015)
  • Medical Education:Perelman School of Medicine University of Pennsylvania (2000) PA
  • Board Certification: Pediatrics, American Board of Pediatrics (2009)
  • Fellowship:Emory University School of Medicine (2009) GA
  • Residency:Children's Hospital of Oakland (2009) CA
  • Fellowship:Childrens Hospital Oakland (2006) CA
  • Internship:Children's Hospital of Oakland (2001) CA
  • Fellowship, Emory University School of Medicine, Pediatric Infectious Diseases (2009)
  • Residency, Children's Hospital & Research Center Oakland, General Pediatrics (2007)
  • M.D., University of Pennsylvania School of Medicine (2000)
  • B.S., University of California, San Diego, Animal Physiology & Neuroscience (1996)

Teaching

Graduate and Fellowship Programs


Publications

All Publications


  • Acute Flavivirus and Alphavirus Infections among Children in Two Different Areas of Kenya, 2015. The American journal of tropical medicine and hygiene Hortion, J., Mutuku, F. M., Eyherabide, A. L., Vu, D. M., Boothroyd, D. B., Grossi-Soyster, E. N., King, C. H., Ndenga, B. A., LaBeaud, A. D. 2018

    Abstract

    Alphaviruses and flaviviruses are known to be endemic in Eastern Africa, but few data are available to evaluate the prevalence of these infections. This leads to missed opportunities for prevention against future outbreaks. This cohort study investigated the frequency of alphavirus and flavivirus incident infections in two regions of Kenya and identified potential risk factors. Seroconversions for alphavirus and flavivirus infections were identified by IgG ELISA in a cohort of 1,604 acutely ill children over the year 2015. The annual incidence was 0.5% (0.2-1.2%) for alphaviruses and 1.2% (0.7-2.2%) for flaviviruses. Overall, seroprevalence was significantly higher for alphaviruses in western Kenya than on the coast (P = 0.014), whereas flavivirus seroprevalence was higher on the coast (P = 0.044). Poverty indicators did not emerge as risk factors, but reliance on household water storage was associated with increased exposure to both alphaviruses and flaviviruses (odds ratio = 2.3).

    View details for DOI 10.4269/ajtmh.18-0297

    View details for PubMedID 30457092

  • Seroepidemiological Studies of Arboviruses in Africa Gudo, E., Ali, S., Antonio, V. S., Chelene, I. R., Chongo, I., Demanou, M., Falk, K., Guiliche, O. C., Heinrich, N., Monteiro, V., Muianga, A. F., Oludele, J., Mula, F., Mutuku, F., Amade, N., Alho, P., Betsem, E., Chimbuinhe, Z., Cristovam, A. J., Galano, G., Gessain, A., Harris, E., Heise, M., Inalda, F., Jala, I., Jaszi, E., King, C., Kitron, U., Kuemmerer, B. M., LaBeaud, A. D., Lagerqvist, N., Malai, G., Mazelier, M., Mendes, S., Mukoko, D., Ndenga, B., Njouom, R., Pinto, G., Tivane, A., Vu, D. M., Vulule, J., Hilgenfeld, R., Vasudevan, S. G. SPRINGER-VERLAG SINGAPORE PTE LTD. 2018: 361–71

    Abstract

    The literature on sero-epidemiological studies of flaviviral infections in the African continent is quite scarce. Much of the viral epidemiology studies have been focussing on diseases such as HIV/AIDS because of their sheer magnitude and impact on the lives of people in the various affected countries. Increasingly disease outbreaks caused by arboviruses such as the recent cases of chikungunya virus, dengue virus and yellow fever virus have prompted renewed interest in studying these viruses. International agencies from the US, several EU nations and China are starting to build collaborations to build capacity in many African countries together with established institutions to conduct these studies. The Tofo Advanced Study Week (TASW) was established to bring the best scientists from the world to the tiny seaside town of Praia do Tofo to rub shoulders with African virologists and discuss cutting-edge science and listen to the work of researchers in the field. In 2015 the 1st TASW focussed on Ebola virus. The collections of abstracts from participants at the 2nd TASW which focused on Dengue and Zika virus as well as presentations on other arboviruses are collated in this chapter.

    View details for DOI 10.1007/978-981-10-8727-1_25

    View details for Web of Science ID 000443965000026

    View details for PubMedID 29845545

  • Unrecognized Dengue Virus Infections in Children, Western Kenya, 2014-2015 EMERGING INFECTIOUS DISEASES Vu, D. M., Mutai, N., Heath, C. J., Vulule, J. M., Mutuku, F. M., Ndenga, B. A., LaBeaud, A. 2017; 23 (11): 1915–17

    Abstract

    We detected a cluster of dengue virus infections in children in Kenya during July 2014-June 2015. Most cases were serotype 1, but we detected all 4 serotypes, including co-infections with 2 serotypes. Our findings implicate dengue as a cause of febrile illness in this population and highlight a need for robust arbovirus surveillance.

    View details for DOI 10.3201/eid2311.170807

    View details for Web of Science ID 000413109500030

    View details for PubMedID 29048283

    View details for PubMedCentralID PMC5652413

  • Principles, practices and knowledge of clinicians when assessing febrile children: a qualitative study in Kenya MALARIA JOURNAL Hooft, A. M., Ripp, K., Ndenga, B., Mutuku, F., Vu, D., Baltzell, K., Masese, L. N., Vulule, J., Mukoko, D., LaBeaud, A. 2017; 16: 381

    Abstract

    Clinicians in low resource settings in malaria endemic regions face many challenges in diagnosing and treating febrile illnesses in children. Given the change in WHO guidelines in 2010 that recommend malaria testing prior to treatment, clinicians are now required to expand the differential when malaria testing is negative. Prior studies have indicated that resource availability, need for additional training in differentiating non-malarial illnesses, and lack of understanding within the community of when to seek care play a role in effective diagnosis and treatment. The objective of this study was to examine the various factors that influence clinician behavior in diagnosing and managing children presenting with fever to health centres in Kenya.A total of 20 clinicians (2 paediatricians, 1 medical officer, 2 nurses, and 15 clinical officers) were interviewed, working at 5 different government-sponsored public clinic sites in two areas of Kenya where malaria is prevalent. Clinicians were interviewed one-on-one using a structured interview technique. Interviews were then analysed qualitatively for themes.The following five themes were identified: (1) Strong familiarity with diagnosis of malaria and testing for malaria; (2) Clinician concerns about community understanding of febrile illness, use of traditional medicine, delay in seeking care, and compliance; (3) Reliance on clinical guidelines, history, and physical examination to diagnose febrile illness and recognize danger signs; (4) Clinician discomfort with diagnosis of primary viral illness leading to increased use of empiric antibiotics; and (5) Lack of resources including diagnostic testing, necessary medications, and training modalities contributes to the difficulty clinicians face in assessing and treating febrile illness in children. These themes persisted across all sites, despite variation in levels of medical care. Within these themes, clinicians consistently expressed a need for reliable basic testing, especially haemograms and bacterial cultures. Clinicians discussed the use of counseling and education to improve community understanding of febrile illness in order to decrease preventable deaths in children.Results of this study suggest that since malarial testing has become more widespread, clinicians working in resource-poor environments still face difficulty when evaluating a child with fever, especially when malaria testing is negative. Improving access to additional diagnostics, continuing medical education, and ongoing evaluation and revision of clinical guidelines may lead to more consistent management of febrile illness by providers, and may potentially decrease prescription of unnecessary antibiotics. Additional interventions at the community level may also have an important role in managing febrile illness, however, more studies are needed to identify targets for intervention at both the clinic and community levels.

    View details for DOI 10.1186/s12936-017-2021-7

    View details for Web of Science ID 000411352400001

    View details for PubMedID 28931399

    View details for PubMedCentralID PMC5607512

  • The role of anti-NHba antibody in bactericidal activity elicited by the meningococcal serogroup B vaccine, MenB-4C VACCINE Partridge, E., Lujan, E., Giuntini, S., Vu, D. M., Granoff, D. M. 2017; 35 (33): 4236–44

    Abstract

    MenB-4C (Bexsero®) is a multicomponent serogroup B meningococcal vaccine. For vaccine licensure, efficacy was inferred from serum bactericidal antibody (SBA) against three antigen-specific indicator strains. The bactericidal role of antibody to the fourth vaccine antigen, Neisserial Heparin binding antigen (NHba), is incompletely understood.We identified nine adults immunized with two or three doses of MenB-4C who had sufficient volumes of sera and >3-fold increases in SBA titer against a strain with high NHba expression, which was mismatched with the other three MenB-4C antigens that elicit SBA. Using 1month-post-immunization sera we measured the effect of depletion of anti-NHba and/or anti-Factor H binding protein (FHbp) antibodies on SBA.Against three strains matched with the vaccine only for NHba, depletion of anti-NHba decreased SBA titers by an average of 43-79% compared to mock-adsorbed sera (P<0.05). Despite expression of sub-family A FHbp (mismatched with the sub-family B vaccine antigen), depletion of anti-FHbp antibodies also decreased SBA by 45-64% (P<0.05). Depletion of both antibodies decreased SBA by 84-100%. Against a strain with sub-family B FHbp and expression of NHba with 100% identity to the vaccine antigen, depletion of anti-NHba decreased SBA by an average of 26%, compared to mock-adsorbed sera (P<0.0001), and depletion of anti-FHbp antibody decreased SBA by 92% (P<0.0001).Anti-NHba antibody can contribute to SBA elicited by MenB-4C, particularly in concert with anti-FHbp antibody. However, some high NHba-expressing strains are resistant, even with an exact match between the amino acid sequence of the vaccine and strain antigens.

    View details for DOI 10.1016/j.vaccine.2017.06.020

    View details for Web of Science ID 000406735500026

    View details for PubMedID 28651840

    View details for PubMedCentralID PMC5560085

  • Chikungunya Virus. Clinics in laboratory medicine Vu, D. M., Jungkind, D., Angelle Desiree LaBeaud 2017; 37 (2): 371-382

    Abstract

    For chikungunya virus (CHIKV), the long-term sequelae from infection are yet ill-defined. The prolonged debilitating arthralgia associated with CHIKV infection has tremendous potential for impacting the global economy and should be considered when evaluating the human burden of disease and the allocation of resources. There is much still unknown about CHIKV and the illnesses that it causes. Developing a better understanding of the pathogenesis of CHIKV infection is a priority and forms the basis for developing effective strategies at infection prevention and disease control.

    View details for DOI 10.1016/j.cll.2017.01.008

    View details for PubMedID 28457355

  • Parasitic Infections in Pregnancy Decrease Placental Transfer of Antipneumococcus Antibodies. Clinical and vaccine immunology McKittrick, N. D., Vu, D. M., Malhotra, I., King, C. H., Mutuku, F., LaBeaud, A. D. 2017; 24 (6)

    Abstract

    Many factors can influence maternal placental antibody transfer to the fetus, which confers important immune protection to the newborn infant. However, little is known about the effect of maternal parasitic infection on placental antibody transfer. To investigate this, we selected, from a parent study of 576 pregnant Kenyan women, four groups of women with term deliveries (≥37 weeks), including uninfected women (N=30) and women with solo infections of malaria (N=30), hookworm (N=30), or schistosomiasis (N=10). Maternal plasma at delivery and infant cord blood were tested via multiplex fluorescent bead assay for IgG against ten pneumococcal serotypes (PnPs 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F), diphtheria toxoid, and Haemophilus influenzae type B. Infants born to mothers with prenatal malaria, hookworm, or S. haematobium infections were associated with a significantly reduced ratio of maternal:infant cord blood antibody concentration for S. pneumoniae serotypes 1, 4, 5, 6B, 7F, 9V, and 18C compared to infants of uninfected mothers. Anti-diphtheria toxoid and anti-H. influenzae type B IgG ratios were not significantly different among infection groups. Prenatal parasitic infections decrease the transfer of maternal IgG antibodies to infants for several serotypes of S. pneumoniae.

    View details for DOI 10.1128/CVI.00039-17

    View details for PubMedID 28404574

  • Pneumococcal Vaccine Response After Exposure to Parasites in Utero, in Infancy, or Mid-Childhood PEDIATRICS Singer, M. N., Heath, C., Muinde, J., Gildengorin, V., Mutuku, F. M., Vu, D., Mukoko, D., King, C. L., Malhotra, I. J., King, C. H., LaBeaud, A. D. 2017; 139 (4)

    Abstract

    Streptococcus pneumoniae is a leading cause of mortality before age 5, but few studies examine details of childhood response to pneumococcal vaccine in less-developed settings. Although malnutrition, HIV, and concurrent infections can impair response, evidence suggests that chronic parasitic infections can also contribute to poor vaccination results. The objective of this study was to determine whether response to pneumococcal vaccine varied among children either exposed to parasitic infections in utero, previously infected in infancy, or infected at the time of immunization.Children from a 2006 to 2010 maternal-infant cohort were eligible for the current study. Children were screened for malaria, schistosomiasis, filariasis, intestinal helminths, and protozoa. Data on in utero exposure and early life infections were linked, and baseline antipneumococcal immunoglobulin G levels and nasopharyngeal carrier status were determined. Participants received decavalent pneumococcal vaccine, and 4 weeks later, serology was repeated to assess vaccine response.A total of 281 children were included. Preimmunity was associated with greater postvaccination increments in anti-pneumococcal polysaccharide immunoglobulin G, especially serotypes 4, 7, 9, 18C, and 19. Present-day growth stunting was independently associated with weaker responses to 1, 4, 6B, 7, 9V, and 19. Previous exposure to Trichuris was associated with stronger responses to 1, 5, 6B, 7, 18C, and 23, but other parasite exposures were not consistently associated with response.In our cohort, hyporesponsiveness to pneumococcal conjugate vaccine was associated with growth stunting but not parasite exposure. Parasite-related vaccine response deficits identified before age 3 do not persist into later childhood.

    View details for DOI 10.1542/peds.2016-2781

    View details for Web of Science ID 000398602400023

    View details for PubMedID 28302673

  • Dengue and West Nile Virus Transmission in Children and Adults in Coastal Kenya AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Vu, D. M., Banda, T., Teng, C. Y., Heimbaugh, C., Muchiri, E. M., Mungai, P. L., Mutuku, F. M., Brichard, J., Gildengorin, G., Borland, E. M., Powers, A. M., Kitron, U., King, C. H., LaBeaud, A. D. 2017; 96 (1): 141-143

    Abstract

    Dengue virus (DENV) and West Nile virus (WNV) are important reemerging arboviruses that are under-recognized in many parts of Africa due to lack of surveillance. As a part of a study on flavivirus, alphavirus, and parasite exposure in coastal Kenya, we measured neutralizing antibody against DENV and, to evaluate assay specificity, WNV in serum samples that tested positive for serum anti-DENV IgG by enzyme-linked immunosorbent assay. Of 830 anti-DENV IgG-positive samples that were tested for neutralizing activity, 488 (58.8%) neutralized DENV and 94 (11.3%) neutralized WNV. Of children ≤ 10 years of age, 23% and 17% had serum neutralizing antibody to DENV and WNV, respectively, indicating that DENV and WNV transmission has occurred in this region within the past decade. The results suggest that ongoing DENV and WNV transmission continues on the coast of Kenya and supports a need for routine arboviral surveillance in the area to detect and respond to future outbreaks.

    View details for DOI 10.4269/ajtmh.16-0562

    View details for Web of Science ID 000397822900025

  • Dengue and West Nile Virus Transmission in Children and Adults in Coastal Kenya. American journal of tropical medicine and hygiene Vu, D. M., Banda, T., Teng, C. Y., Heimbaugh, C., Muchiri, E. M., Mungai, P. L., Mutuku, F. M., Brichard, J., Gildengorin, G., Borland, E. M., Powers, A. M., Kitron, U., King, C. H., LaBeaud, A. D. 2016

    Abstract

    Dengue virus (DENV) and West Nile virus (WNV) are important reemerging arboviruses that are under-recognized in many parts of Africa due to lack of surveillance. As a part of a study on flavivirus, alphavirus, and parasite exposure in coastal Kenya, we measured neutralizing antibody against DENV and, to evaluate assay specificity, WNV in serum samples that tested positive for serum anti-DENV IgG by enzyme-linked immunosorbent assay. Of 830 anti-DENV IgG-positive samples that were tested for neutralizing activity, 488 (58.8%) neutralized DENV and 94 (11.3%) neutralized WNV. Of children ≤ 10 years of age, 23% and 17% had serum neutralizing antibody to DENV and WNV, respectively, indicating that DENV and WNV transmission has occurred in this region within the past decade. The results suggest that ongoing DENV and WNV transmission continues on the coast of Kenya and supports a need for routine arboviral surveillance in the area to detect and respond to future outbreaks.

    View details for PubMedID 27821697

  • Inhibition of the Alternative Pathway of Nonhuman Infant Complement by Porin B2 Contributes to Virulence of Neisseria meningitidis in the Infant Rat Model INFECTION AND IMMUNITY Lewis, L. A., Vu, D. M., Granoff, D. M., Ram, S. 2014; 82 (6): 2574-2584

    Abstract

    Neisseria meningitidis utilizes capsular polysaccharide, lipooligosaccharide (LOS) sialic acid, factor H binding protein (fHbp), and neisserial surface protein A (NspA) to regulate the alternative pathway (AP) of complement. Using meningococcal mutants that lacked all four of the above-mentioned molecules (quadruple mutants), we recently identified a role for PorB2 in attenuating the human AP; inhibition was mediated by human fH, a key downregulatory protein of the AP. Previous studies showed that fH downregulation of the AP via fHbp or NspA is specific for human fH. Here, we report that PorB2-expressing quadruple mutants also regulate the AP of baby rabbit and infant rat complement. Blocking a human fH binding region on PorB2 of the quadruple mutant of strain 4243 with a chimeric protein that comprised human fH domains 6 and 7 fused to murine IgG Fc enhanced AP-mediated baby rabbit C3 deposition, which provided evidence for an fH-dependent mechanism of nonhuman AP regulation by PorB2. Using isogenic mutants of strain H44/76 that differed only in their PorB molecules, we confirmed a role for PorB2 in resistance to killing by infant rat serum. The PorB2-expressing strain also caused higher levels of bacteremia in infant rats than its isogenic PorB3-expressing counterpart, thus providing a molecular basis for increased survival of PorB2 isolates in this model. These studies link PorB2 expression with infection of infant rats, which could inform the choice of meningococcal strains for use in animal models, and reveals, for the first time, that PorB2-expressing strains of N. meningitidis regulate the AP of baby rabbits and rats.

    View details for DOI 10.1128/IAI.01517-14

    View details for Web of Science ID 000336378100042

    View details for PubMedID 24686052

  • Fusion protein comprising factor H domains 6 and 7 and human IgG1 Fc as an antibacterial immunotherapeutic. Clinical and vaccine immunology : CVI Shaughnessy, J., Vu, D. M., Punjabi, R., Serra-Pladevall, J., DeOliveira, R. B., Granoff, D. M., Ram, S. 2014; 21 (10): 1452–59

    Abstract

    The emergence of antimicrobial resistance among several medically important pathogens represents a serious threat to human health globally and necessitates the development of novel therapeutics. Complement forms a key arm of innate immune defenses against invading pathogens. A mechanism of complement evasion employed by many pathogens is binding of complement inhibitors, including factor H (FH), a key downregulator of the alternative pathway. Most FH-binding bacteria engage FH through regions in FH spanned by domains 6 and 7 and/or 18 through 20. We created a chimeric protein that comprised human FH domains 6 and 7 fused to human IgG1 Fc (FH6,7/HuFc) and tested its activity as an immunotherapeutic against Neisseria meningitidis, which binds FH through domains 6 and 7. FH6,7/HuFc bound to meningococci and effectively blocked FH binding to bacteria. FH6,7/HuFc enhanced human C3 and C4 deposition and facilitated complement-mediated killing in a dose-responsive manner; complement activation and killing were classical pathway dependent. To investigate in vivo efficacy, infant Wistar rats were treated intraperitoneally (IP) with different doses of FH6,7/HuFc and challenged 2 h later with serogroup C strain 4243 given IP. At 8 to 9 h after the challenge, the FH6,7/HuFc-treated rats had >100-fold fewer CFU per ml of blood than control animals pretreated with phosphate-buffered saline (PBS) or FH18-20/HuFc, which does not bind to meningococci (P < 0.0001). These data provide proof of concept of the utility of FH/Fc fusion proteins as anti-infective immunotherapeutics. Because many microbes share a common binding region(s) in FH, FH/Fc chimeric proteins may be a promising candidate for adjunctive therapy against drug-resistant pathogens.

    View details for DOI 10.1128/CVI.00444-14

    View details for PubMedID 25143339

  • Factor H-Dependent Alternative Pathway Inhibition Mediated by Porin B Contributes to Virulence of Neisseria meningitidis MBIO Lewis, L. A., Vu, D. M., Vasudhev, S., Shaughnessy, J., Granoff, D. M., Ram, S. 2013; 4 (5)

    Abstract

    The identification of "factor H binding protein (fHbp)-null" invasive meningococcal isolates and the realization that widespread use of fHbp-based vaccines could herald selection of such strains prompted us to characterize novel mechanisms of alternative pathway (AP) inhibition on meningococci. Of seven strains engineered to lack four known AP-inhibiting molecules, capsular polysaccharide, lipooligosaccharide sialic acid, fHbp, and neisserial surface protein A (quadruple mutants), four strains inhibited human AP-mediated C3 deposition. All four expressed the porin B2 (PorB2) molecule, and three strains belonged to the hypervirulent ST-11 lineage. Consistent with reduced C3 deposition, the rate of C3a generation by a PorB2 isolate was lower than that by a PorB3 strain. Allelic replacement of PorB3 with PorB2, in both encapsulated and unencapsulated strains, confirmed the role of PorB2 in AP inhibition. Expression of PorB2 increased resistance to complement-dependent killing relative to that seen in an isogenic PorB3-expressing strain. Adult rabbit and mouse APs were unimpeded on all mutants, and human fH inhibited nonhuman C3 deposition on PorB2-expressing strains, which provided functional evidence for human fH-dependent AP regulation by PorB2. Low-affinity binding of full-length human fH to quadruple mutants expressing PorB2 was demonstrated. fH-like protein 1 (FHL-1; contains fH domains 1 through 7) and fH domains 6 and 7 fused to IgG Fc bound to one PorB2-expressing quadruple mutant, which suggested that fH domains 6 and 7 may interact with PorB2. These results associate PorB2 expression with serum resistance and presage the appearance of fHbp-null and hypervirulent ST-11 isolates that may evade killing by fHbp-based vaccines.The widespread use of antimeningococcal vaccines based on factor H (fH) binding protein (fHbp) is imminent. Meningococci that lack fHbp were recently isolated from persons with invasive disease, and these fHbp-null strains could spawn vaccine failure. Our report provides a molecular basis for an explanation of how fHbp-null strains may evade the host immune system. Meningococci possess several mechanisms to subvert killing by the alternative pathway (AP) of complement, including production of the fHbp and NspA fH binding proteins. Here we show that a meningococcal protein called porin B2 (PorB2) contributes to inhibition of the AP on the bacterial surface. A majority of the "fHbp-null" isolates identified, as well as all members of a "hypervirulent" lineage (called ST-11), express PorB2. Our findings highlight the potential for the emergence of fHbp-negative strains that are able to regulate the AP and may be associated with fHbp vaccine failure.

    View details for DOI 10.1128/mBio.00339-13

    View details for Web of Science ID 000326881800002

    View details for PubMedID 24129254

  • fH-dependent complement evasion by disease-causing meningococcal strains with absent fHbp genes or frameshift mutations VACCINE Giuntini, S., Vu, D. M., Granoff, D. M. 2013; 31 (38): 4192-4199

    Abstract

    Meningococci bind human fH to down-regulate complement, which enhances survival of the bacteria in serum. A major fH ligand is the vaccine candidate, factor H-binding protein (fHbp). Although fHbp has been considered an essential meningococcal virulence factor, rarely, invasive isolates with absent fHbp genes or frameshift mutations have been identified. In previous studies fH binding to these isolates was not detected. The aim of the present study was to investigate fH binding and complement evasion by invasive meningococcal serogroup B clinical isolates with absent fHbp genes or frameshift mutations. Four of the seven isolates tested bound human fH by flow cytometry and survived in IgG-depleted human serum. In all four, fH binding was decreased after inactivating the gene encoding NspA. Binding of fH to fHbp and NspA is specific for human fH. To investigate fH-dependent evasion of host defenses, human fH transgenic infant rats, or control littermates negative for human fH, were challenged IP with 10(3)-10(4)CFU of two of the isolates with no detectable fH binding by flow cytometry. At 6h, bacteremia caused by both strains was higher in human fH transgenic rats than in control rats (P<0.002). In conclusion, six of the seven isolates had evidence of fH binding and/or human fH-dependent complement evasion in transgenic rats. In four, NspA was as an alternative fH ligand. fHbp vaccination may select for mutants that do not require fHbp for complement evasion. Inclusion of additional target antigens in vaccines containing fHbp may delay emergence of these mutants.

    View details for DOI 10.1016/j.vaccine.2013.06.009

    View details for Web of Science ID 000323591400022

    View details for PubMedID 23791680

    View details for PubMedCentralID PMC3756549

  • A Broadly Cross-Reactive Monoclonal Antibody Against an Epitope on the N-terminus of Meningococcal fHbp SCIENTIFIC REPORTS Vu, D. M., Pajon, R., Reason, D. C., Granoff, D. M. 2012; 2

    Abstract

    Meningococcal factor H binding protein (fHbp) is an important vaccine antigen for prevention of disease caused by capsular group B strains. The protein has been sub-classified into three variant groups. Most anti-fHbp antibodies are variant group-specific and recognize epitopes on the C-terminal domain. We report a murine IgG1 mAb, JAR 41, which broadly cross-reacted with fHbp sequence variants from all variant groups. The mAb bound to the surface of live meningococci with fHbp from each of the three variant groups. In combination with second non-bactericidal anti-fHbp mAbs, JAR 41 elicited complement-mediated bactericidal activity in vitro, and augmented passive protection against meningococcal bacteremia in human fH transgenic rats. The epitope was located on a conserved region of the N-terminal portion of the fHbp molecule opposite that of fH contact residues. The data underscore the importance of broadly cross-reactive, surface-exposed epitopes on the N-terminal domain in the design of protective fHbp vaccines.

    View details for DOI 10.1038/srep00341

    View details for Web of Science ID 000302126600003

    View details for PubMedID 22461972

    View details for PubMedCentralID PMC3314305

  • Enhanced Bacteremia in Human Factor H Transgenic Rats Infected by Neisseria meningitidis INFECTION AND IMMUNITY Vu, D. M., Shaughnessy, J., Lewis, L. A., Ram, S., Rice, P. A., Granoff, D. M. 2012; 80 (2): 643-650

    Abstract

    Neisseria meningitidis binds the complement downregulating protein, factor H (fH), which enables the organism to evade host defenses. Two fH ligands, fHbp and NspA, are known to bind specifically to human fH. We developed a human fH transgenic infant rat model to investigate the effect of human fH on meningococcal bacteremia. At 18 h after intraperitoneal challenge with 560 CFU of group B strain H44/76, all 19 human fH-positive rats had positive blood cultures compared to 0 of 7 human fH-negative control littermates (P < 0.0001). Human fH-positive infant rats also developed bacteremia after challenge with isogenic mutants of H44/76 in which genes encoding fHbp and NspA (ΔfHbp ΔNspA mutant) or the lipooligosaccharide sialyltransferase (Δlst mutant) had been inactivated. A fully encapsulated ΔfHbp ΔNspA Δlst mutant unable to sialylate lipooligosaccharide or bind human fH via the known fH ligands did not cause bacteremia, which argued against global susceptibility to bacteremia resulting from random integration of the transgene into the rat genome. In vitro, the wild-type and ΔfHbp ΔNspA mutant strains were killed by as little as 20% wild-type infant rat serum. The addition of 3 μg of human fH/ml permitted survival of the wild-type strain in up to 60% infant rat serum, whereas ≥33 μg of human fH/ml was required to rescue the ΔfHbp ΔNspA mutant. The ability of meningococci lacking expression of fHbp and NspA to cause invasive disease in human fH transgenic rats and to survive in wild-type infant rat serum supplemented with human fH indicates an additional human fH-dependent mechanism of evasion of innate immunity.

    View details for DOI 10.1128/IAI.05604-11

    View details for Web of Science ID 000299661200017

    View details for PubMedID 22104107

    View details for PubMedCentralID PMC3264313

  • Cooperative serum bactericidal activity between human antibodies to meningococcal factor H binding protein and Neisserial heparin binding antigen VACCINE Vu, D. M., Wong, T. T., Granoff, D. M. 2011; 29 (10): 1968-1973

    Abstract

    A meningococcal group B vaccine containing multiple protein antigens including factor H binding protein (fHbp) and Neisserial heparin binding antigen (NHba) is in clinical development. The ability of antibodies against individual antigens to interact and augment protective immunity is unknown. We assayed human complement-mediated bactericidal activity (SBA) in stored sera from six immunized adults before and after depletion of antibodies to fHbp and/or NHba. All six subjects developed ≥ 4-fold increases in SBA titer against a test strain with fHbp in the variant 1 group with an amino acid sequence that matched the vaccine antigen (GMT <1:4 baseline, to 1:139 after 3 doses of vaccine). By adsorption 88 to >95% of the SBA was directed against fHbp. Four subjects developed ≥ 4-fold increases in SBA titer against a test strain with a heterologous fHbp variant 2 antigen and a homologous NHba amino acid sequence that matched the vaccine antigen (GMT <1:4 baseline, to 1:45). SBA was directed primarily against NHba in one subject, against fHbp in a second, while depletion of either anti-NHba or anti-fHbp antibody removed the majority of SBA in sera from two subjects. In all four subjects, depletion of both anti-fHbp and anti-NHba antibodies removed more SBA than depletion of either antibody individually. Mixing a mouse non-bactericidal anti-fHbp variant 1 antiserum with a mouse anti-NHba antiserum also augmented the anti-NHba SBA titer against this test strain. For meningococcal vaccines that target relatively sparsely exposed antigens such fHbp or NHba, non-bactericidal antibodies against individual antigens can cooperate and elicit SBA.

    View details for DOI 10.1016/j.vaccine.2010.12.075

    View details for Web of Science ID 000288730500016

    View details for PubMedID 21241734

    View details for PubMedCentralID PMC3043162

  • NEISSERIA SICCA/SUBFLAVA BACTEREMIA PRESENTING AS CUTANEOUS NODULES IN AN IMMUNOCOMPROMISED HOST PEDIATRIC INFECTIOUS DISEASE JOURNAL Jung, J. J., Vu, D. M., Clark, B., Keller, F. G., Spearman, P. 2009; 28 (7): 661-663

    Abstract

    Neisseria sicca/subflava are generally considered commensal inhabitants of the human oropharynx. We describe a case of disseminated N. sicca/subflava infection in an immunocompromised 15-year-old male presenting with cutaneous erythematous nodules. Our report adds to the growing evidence that these bacteria can cause disseminated infections, and describes a cutaneous manifestation of disseminated disease with N. sicca/subflava.

    View details for DOI 10.1097/INF.0b013e318196bd48

    View details for Web of Science ID 000267409900026

    View details for PubMedID 19483662

  • Group A antibody persistence five years after meningococcal polysaccharide vaccination in the Sudan HUMAN VACCINES Flitter, B. A., Ismail, A., Vu, D., Granoff, D. M. 2007; 3 (4): 135-138

    Abstract

    Large meningococcal group A epidemics occur periodically in the Sudan, a country within the "meningitis belt" of Sub-Saharan Africa. Immunization with meningococcal polysaccharide vaccine induces protective serum bactericidal titers but little information is available on the duration of protection. Serum samples were obtained from 20 subjects, aged 11-47 years, who resided in the Sudan, and who had participated in a meningococcal polysaccharide immunogenicity study five years earlier. Persistence of serum group A bactericidal titers (measured with human complement) was compared to that of 12 immunized adults in North America with no known exposure to group A organisms. One month after vaccination, there were no significant differences in the serum bactericidal titers of the two groups. By five years the respective reciprocal geometric mean bactericidal titers had declined in both groups (82 to 34 in Sudanese, and 69-11 in North Americans, p < or = 0.03). However, the proportion of sera with protective bactericidal titers (> or =1:4) at five years was higher in the Sudanese than North Americans (80% vs. 42%, p < or = 0.05). Recommendations for periodic meningococcal polysaccharide vaccination every 3-5 years to maintain group A immunity may be more appropriate for persons living outside of endemic areas than for persons residing in endemic regions since immunity in endemic areas can be maintained by periodic exposure to group A organisms, even during periods between epidemics.

    View details for Web of Science ID 000249860700006

    View details for PubMedID 17581284

  • Effectiveness analyses may underestimate protection of infants after group C meningococcal immunization 45th Interscience Conference on Antimicrobial Agents and Chemotherapy Vu, D. M., Kelly, D., Heath, P. T., McCarthy, N. D., Pollard, A. J., Granoff, D. M. OXFORD UNIV PRESS INC. 2006: 231–37

    Abstract

    Group C meningococcal conjugate-vaccine effectiveness in the United Kingdom declines from ~90% in the first year to 0% between 1 and 4 years after immunization in infants immunized at 2, 3, and 4 months of age and to 61% in toddlers given a single dose. Confidence intervals are wide, and the extent of protection is uncertain.Serum samples were obtained from children 3-5 years of age who were participants in a preschool booster-vaccine trial. Serum bactericidal activity was measured with human complement. Group C anticapsular antibody concentrations were measured by a radioantigen binding assay. Passive protection was analyzed in an infant rat bacteremia model.Serum samples from UK children who had been immunized 2-3 years earlier as infants or toddlers had higher levels of radioantigen binding, bactericidal activity, and passive protection than did historical control serum samples from unimmunized children (P<.05). A higher proportion of children immunized as infants had serum bactericidal activity titers > or =1 : 4 (considered to be protective) than those immunized as toddlers (61% vs. 24%; P<.01), but there were no significant differences in the proportion of serum samples conferring passive protection (50% and 41%, respectively; P=.4).We found no evidence of lower immunity in children immunized as infants than as toddlers. On the basis of serum bactericidal activity and/or passive protection, 40%-50% of both age groups are protected at 2-3 years after immunization, which was significantly greater than in unimmunized historical controls (<5%).

    View details for Web of Science ID 000238337600014

    View details for PubMedID 16779730

  • Priming for immunologic memory in adults by meningococcal group C conjugate vaccination CLINICAL AND VACCINE IMMUNOLOGY Vu, D. M., de Boer, A. W., Danzig, L., Santos, G., Canty, B., Flores, B. M., Granoff, D. A. 2006; 13 (6): 605-610

    Abstract

    Meningococcal group C polysaccharide-protein conjugate vaccines (MCV) prime infants and children for memory anticapsular responses upon subsequent exposure to unconjugated polysaccharide. The objective of this study was to determine whether MCV primes vaccine-naïve adults and adults previously vaccinated with meningococcal polysaccharide vaccine (MPSV) for memory antibody responses. Meningococcal vaccine-naïve adults were randomized to receive either MCV (MCV/naïve group) (n = 35) or pneumococcal conjugate vaccine (PCV) (PCV/naïve group) (n = 34). Participants with a history of receiving MPSV were given MCV (MCV/MPSV group) (n = 26). All subjects were challenged 10 months later with one-fifth of the usual dose of MPSV (10 mug of each polysaccharide). Sera were obtained before the conjugate vaccination and before and 7 days after the MPSV challenge and assayed for immunoglobulin G (IgG) anticapsular antibody concentrations and bactericidal titers. The MCV/naïve group had 7- to 10-fold-higher serum IgG and bactericidal responses after the MPSV challenge than the PCV/naïve group (P < 0.001). The increases (n-fold) in anticapsular antibody concentrations in the MCV/naïve group were greatest in subjects with antibody concentrations of 2 microg/ml before the challenge; P < 0.0001). Only 3 of 11 MCV-vaccinated subjects who had received MPSV before enrollment and who had antibody concentrations of

    View details for DOI 10.1128/CVI.00123-06

    View details for Web of Science ID 000238337900001

    View details for PubMedID 16760316

    View details for PubMedCentralID PMC1489557

  • Antibody persistence 3 years after immunization of adolescents with quadrivalent meningococcal conjugate vaccine 43rd Annual Meeting of the Infectious-Diseases-Society-of-America Vu, D. M., Welsch, J. A., Zuno-Mitchell, P., Dela Cruz, J. V., Granoff, D. M. UNIV CHICAGO PRESS. 2006: 821–28

    Abstract

    A quadrivalent meningococcal conjugate vaccine (MCV-4) is recommended for United States teenagers. The duration of protective immunity is unknown. We investigated serum antibody persistence 3 years after vaccination of adolescents.Serum samples from participants of a randomized trial who had received MCV-4 (n=52) or polysaccharide vaccine (MPSV-4; n=48) and from unvaccinated controls (n=60) were assayed for serogroups C, W-135, and Y anticapsular antibody concentrations by use of a radioantigen binding assay and for bactericidal activity (in a human complement assay) and passive protection against serogroup C bacteremia in an infant rat model.A higher proportion of participants in the vaccine groups had protective bactericidal titers (> or =1 : 4), compared with that in the control group (for MCV-4 recipients vs. controls, P<.01; for MPSV-4 recipients vs. controls, P< or =.06). More MCV-4 recipients had W-135 bactericidal titers > or =1 : 4 than did MPSV-4 recipients (P=.01). More MCV-4 recipients had passive protective activity against serogroup C bacteremia than did MPSV-4 recipients (76% vs. 49%; P<.01). The differences in protective activity were largest between participants in the vaccine groups with bactericidal titers <1 : 4 (63% protective in MCV-4 recipients vs. 31% protective in MPSV-4 recipients; P=.01).Compared with MPSV-4, MCV-4 elicited greater persistence of antibody activity against serogroups C and W-135 at 3 years after vaccination in adolescents. On the basis of passive protection data in an infant rat model, bactericidal titers > or =1 : 4 underestimate protective immunity.

    View details for Web of Science ID 000235536200013

    View details for PubMedID 16479517