Measles Virus-Specific CD4 T-Cell Activity Does Not Correlate with Protection against Lung Infection or Viral Clearance

Measles remains an important cause of pediatric morbidity and mortality in developing countries, especially among infants who are too young to receive the current licensed live attenuated measles vaccine. We developed two Sindbis virus DNA vaccines encoding the measles virus hemagglutinin (pMSIN-H) and fusion proteins (pMSINH-FdU) and examined their immunogenicities and protective efficacies when administered alone or followed by the live measles virus vaccine in cotton rats. Neutralizing antibodies, mucosal and systemic antibody-secreting cells, memory B cells, and gamma interferon-secreting T cells developed after priming and increased after boosting. pMSIN-H priming conferred 100% protection against pulmonary measles, whereas pMSINH-FdU protected only in conjunction with the live measles virus vaccine boost.

mentioning

confidence: 61%

Sindbis Virus-Based Measles DNA Vaccines Protect Cotton Rats against Respiratory Measles: Relevance of Antibodies, Mucosal and Systemic Antibody-Secreting Cells, Memory B Cells, and Th1-Type Cytokines as Correlates of Immunity

Pasetti

Ramírez

Reséndiz-Albor

et al. 2009

“…Studies in both cotton rats and humans have demonstrated that immunization in the presence of MV-specific IgG (maternal antibodies) results in the induction of MV-specific T cells, whereas the generation of neutralizing antibodies is inhibited (12)(13)(14)31). Suppression of the antibody response could be due to inhibition of the generation of MVspecific B cells or to a lack of antibody secretion after immunization in the presence of maternal antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…One obvious example is acute measles, where early immunization is imperative and failure to do so results in approximately 200,000 deaths every year worldwide. In humans (12)(13)(14) (as well as in cotton rats [31]), it was shown that the development of neutralizing antibodies is impaired, whereas T-cell proliferation is still detectable after immunization in the presence of maternal antibodies. This is significant, because only neutralizing antibodies protect against infection (for a review, see reference 24).…”

mentioning

confidence: 99%

Induction of Type I Interferon Secretion through Recombinant Newcastle Disease Virus Expressing Measles Virus Hemagglutinin Stimulates Antibody Secretion in the Presence of Maternal Antibodies

Kim

Martínez-Sobrido

Choi

et al. 2011

Self Cite

Measles virus (MV) vaccine effectively protects seronegative individuals against infection. However, inhibition of vaccine-induced seroconversion by maternal antibodies after vaccination remains a problem, as it leaves infants susceptible to MV infection. In cotton rats, passive transfer of MV-specific IgG mimics maternal antibodies and inhibits vaccine-induced seroconversion. Here, we report that immunization in the presence of passively transferred IgG inhibits the secretion of neutralizing antibodies but not the generation of MV-specific B cells. This finding suggested that MV-specific B cells require an additional stimulus to mature into antibody-secreting plasma cells. In order to provide such a stimulus, we generated a recombinant Newcastle disease virus (NDV) expressing the MV hemagglutinin (NDV-H). In contrast to MV, NDV-H induced high levels of type I interferon in plasmacytoid dendritic cells and in lung tissue. In cotton rats immunized with NDV-H, neutralizing antibodies were also generated in the presence of passively transferred antibodies. In the latter case, however, the level and kinetics of antibody generation were reduced. In vitro, alpha interferon stimulated the activation of MV-specific B cells from MV-immune spleen cells. NDV infection (which induces alpha interferon) had the same effect, and stimulation could be abrogated by antibodies neutralizing alpha interferon, but not interleukin 6 (IL-6). In vivo, coapplication of UV-inactivated MV with NDV led to increased MV-specific antibody production in the presence and absence of passively transferred antibodies. These data indicate that MV-specific B cells are being generated after immunization in the presence of maternal antibodies and that the provision of alpha interferon as an additional signal leads to antibody secretion.

“…The products of the reaction were subjected to reducing SDS-PAGE gels and silver stained as described in Materials and Methods. rats (CR) mimics natural infection (70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83). MV replicates in CR lung tissue with peak titers occurring on day 4 or 5, and infection is overcome by day 8.…”

Section: Hpiv3 F-derived Hrc Peptides Inhibit Wt MV Entrymentioning

confidence: 99%

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Mathieu

Huey

Jurgens

et al. 2015

100

Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV H and the fusion (F) envelope glycoprotein; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad-repeat (HR) regions of F can potently inhibit MV infection at the entry stage. We show here that specific features of H's interaction with its receptors modulate the susceptibility of MV F to peptide fusion inhibitors. A higher concentration of inhibitory peptides is required to inhibit F-mediated fusion when H is engaged to its nectin-4 receptor than when H is engaged to its CD150 receptor. Peptide inhibition of F may be subverted by continued engagement of receptor by H, a finding that highlights the ongoing role of H-receptor interaction after F has been activated and that helps guide the design of more potent inhibitory peptides. Intranasal administration of these peptides results in peptide accumulation in the airway epithelium with minimal systemic levels of peptide and efficiently prevents MV infection in vivo in animal models. The results suggest an antiviral strategy for prophylaxis in vulnerable and/or immunocompromised hosts. IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS)and severe neurological disease. No specific treatment is available. We have shown that parenterally delivered fusion-inhibitory peptides protect mice from lethal CNS MV disease. Here we show, using established small-animal models of MV infection, that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. Since the fusion inhibitors are stable at room temperature, this intranasal strategy is feasible even outside health care settings, could be used to protect individuals and communities in case of MV outbreaks, and could complement global efforts to control measles.