Neonatal Immunization with a Sindbis Virus-DNA Measles Vaccine Induces Adult-Like Neutralizing Antibodies and Cell-Mediated Immunity in the Presence of Maternal Antibodies

Abstract

Infants younger than age 9 mo do not respond reliably to the live attenuated measles vaccine due the immaturity of their immune system and the presence of maternal Abs that interfere with successful immunization. We evaluated the immune responses elicited by Sindbis virus replicon-based DNA vaccines encoding measles virus (MV) hemagglutinin (H, pMSIN-H) or both hemagglutinin and fusion (F, pMSINH-FdU) glycoproteins in neonatal mice born to naive and measles-immune mothers. Despite the presence of high levels of maternal Abs, neonatal immunization with pMSIN-H induced long-lasting, high-avidity MV plaque reduction neutralization (PRN) Abs, mainly IgG2a, that also inhibited syncytium formation in CD150+ B95-8 cells. IgG secreting plasma cells were detected in spleen and bone marrow. Newborns vaccinated with pMSINH-FdU elicited PRN titers that surpassed the protective level (200 mIU/ml) but were short-lived, had low syncytium inhibition capacity, and lacked avidity maturation. This vaccine failed to induce significant PRN titers in the presence of placentally transferred Abs. Both pMSIN-H and pMSINH-FdU elicited strong Th1 type cell-mediated immunity, measured by T cell proliferation and IFN-γ production, that was unaffected by maternal Abs. Newborns responded to measles DNA vaccines with similar or even higher PRN titers and cell-mediated immunity than adult mice. This study is the first demonstration that a Sindbis virus-based measles DNA vaccine can elicit robust MV immunity in neonates bypassing maternal Abs. Such a vaccine could be followed by the current live attenuated MV vaccine in a heterologous prime-boost to protect against measles early in life.

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

“…The results described in this study corroborate those reported for other animal species (5,16,21). The superior immunogenicity of pMSIN-H over pMSINHF-dU, for example, has now been confirmed in several animal models.…”

“…Both vaccines were highly immunogenic for adult and newborn mice, even in the presence of maternal antibodies (5,15,21). They also elicited high levels of neutralizing antibodies in juvenile and infant rhesus macaques and protected them against respiratory challenge.…”

“…Lung tissue was dissected and homogenized and lymphocytes further purified through gradient centrifugation using Lympholyte (rat) (4). Cells from spleen and bone marrow (BM) were obtained as described previously (5). Peripheral blood lymphocytes (PBL) were separated from heparinized blood through gradient centrifugation.…”

An Immunogenic and Protective Alphavirus Replicon Particle-Based Dengue Vaccine Overcomes Maternal Antibody Interference in Weanling Mice

“…Preclinical studies of neonatal DNA vaccination highlight potential advantages of this vector for earlylife immunizations (6). Immunization of neonatal mice with a Sindbis virus DNA measles vaccine induced adult-like neutralizing antibodies and cell-mediated immunity in the presence of maternal antibodies (8). Human adenovirus 5 recombinant viruses expressing the HA and the nucleoprotein of swine influenza virus successfully defeated the suppressive effects of maternal-antibody interference (64), and replication-defective adenovirus expressing rabies glycoproteins in mice resulted in the induction of an endogenous immune response not impaired by maternal immunity (62).…”

Mucosal co-immunization with AIM2 enhances protective SIgA response and increases prophylactic efficacy of chitosan-DNA vaccine against coxsackievirus B3-induced myocarditis

“…56 Briefly, fecal samples (in 2-fold dilution) were tested in duplicate plates. In one of the plates, 6M urea (Sigma) was added after incubation with samples and incubated for 10 min.…”