Influence of maternal antibodies on vaccine responses: inhibition of antibody but not T cell responses allows successful early prime-boost strategies in mice

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.

Section: Discussionsupporting

confidence: 55%

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

Capozzo

Ramírez

Polo

et al. 2006

“…However, they have been identified infrequently as contributors to protection against reinfection with RSV, and the resistance mediated by RSVspecific CD8 ϩ T cells appears short-lived (2). The T cell-mediated mechanism of resistance identified in this paper may apply to other virus infections of infants who require immunization in the presence of maternal Abs, such as measles virus and influenza virus (41,46,47). Such studies with other viruses taken together with our data suggest that immunization with live respiratory viruses mediate protection by a novel T cell mechanism requiring the cooperation of CD4 ϩ and CD8 ϩ T cells when the usual mechanism of protection, i.e., neutralizing Abs, is suppressed.…”

Section: Discussionmentioning

confidence: 90%

“…Passively acquired Abs suppress the primary Ab response to immunization with live RSV vaccine candidates, RSV subunit vaccines, or vaccinia-RSV recombinant viruses (20,21,32). Indeed, suppression of infant humoral responses by maternal Abs has been demonstrated for a wide variety of vaccines, including bacterial vaccines, such as pertussis (33) or tetanus vaccines (34) and viral vaccines such as those for rabies virus (35), canine parvovirus (36), pseudorabies virus (37,38), foot and mouth disease virus (39), feline rhinotracheitis virus (40), and measles virus (41,42). However, it was possible to protect chimpanzees by immunization with live attenuated RSV vaccine even when the induction of serum neutralizing Abs by the vaccine was suppressed by the passively acquired RSV Abs (21).…”

Section: Discussionmentioning

confidence: 99%

Passively Acquired Antibodies Suppress Humoral But Not Cell-Mediated Immunity in Mice Immunized with Live Attenuated Respiratory Syncytial Virus Vaccines

Crowe

Firestone

Murphy

2001

A respiratory syncytial virus (RSV) vaccine will need to be administered by 1 mo of age to protect young infants; therefore, it will need to be effective in the presence of maternally acquired RSV Abs. In the present study, the immunogenicity and efficacy of two live attenuated RSV vaccine candidates of different level of attenuation were evaluated in mice passively immunized with varying quantities of RSV Abs. The replication of the RSV vaccines was suppressed in the lower, but not the upper, respiratory tract of the passively immunized mice. Immunization with either vaccine candidate was highly efficacious against challenge with wild-type RSV in both passively immunized and control mice. Nonetheless, a high level of immunity was seen even in passively/actively immunized animals that failed to develop a humoral immune response, suggesting that T cells mediated the immunity. Depletion of CD4+ and CD8+ T cells in passively/actively immunized and control animals at the time of challenge with wild-type RSV demonstrated that CD4+ and CD8+ T cells made significant independent contributions to the restriction of replication of RSV challenge virus in both the upper and lower respiratory tracts. Although passively acquired serum RSV Abs suppressed the primary systemic and mucosal Ab responses of IgM, IgG, and IgA isotypes, B lymphocytes were nevertheless primed for robust secondary Ab responses. Thus, immunity mediated by CD4+ and CD8+ T cells and Abs can be readily induced in mice by live RSV vaccine candidates in the presence of physiologic levels of RSV neutralizing Abs.

“…A second aspect of the explanation could lie with interference by pre-existing immunity. Thus, for example, DNA vaccines appear unaffected by pre-existing immunity (27,28). This makes then potentially valuable vaccines in animals, such as newborns that possess high levels of passive immunity (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, for example, DNA vaccines appear unaffected by pre-existing immunity (27,28). This makes then potentially valuable vaccines in animals, such as newborns that possess high levels of passive immunity (28,29). In contrast, immune responses to attenuated vaccines can be limited by pre-existing immunity (27)(28)(29), although in the case of recombinant vaccinia virus vectors this effect may be less when vaccines are administered mucosally (25).…”

Section: Discussionmentioning

confidence: 99%

Prime-Boost Immunization with DNA Vaccine: Mucosal Route of Administration Changes the Rules

Gieryńska

Kamar

et al. 2001

In this study we assessed prime-boost immunization strategies with a DNA vaccine (gB DNA) and attenuated recombinant vaccinia virus vector (rvacgB), both encoding the gB protein of HSV, for their effectiveness at inducing mucosal as well as systemic immunity to HSV. Confirming the reports of others, systemic priming with gB DNA and systemic boosting with rvacgB were the most effective means of inducing serum Ab and splenic T cell responses. Nevertheless, the systemic prime-boost approach failed to induce detectable humoral or T cell responses at mucosal sites. However, such responses, at both proximal and distal locations, were induced if immunizations, especially the priming dose, were administered mucosally. Curiously, whereas optimal immunity with systemic priming and boosting occurred when gB DNA was used to prime and rvacgB was used as a boost, mucosal responses were optimal when animals were mucosally primed with rvacgB and boosted with gB DNA given mucosally. Furthermore, notable mucosal responses also occurred in animals mucosally primed with rvacgB and subsequently boosted systemically with gB DNA. Because the mucosal prime-boost immunization protocol also induced excellent systemic immune responses, the approach should be useful to vaccinate against agents for which both mucosal and systemic immunity are important for protection.