Biomedical subjects

Bror Morein

Publications and source records attributed to Bror Morein.

12 recordsLinked to original sources

PubMed2006

High titers of circulating maternal antibodies suppress effector and memory B-cell responses induced by an attenuated rotavirus priming and rotavirus-like particle-immunostimulating complex boosting vaccine regimen.

We investigated maternal antibody (MatAb) effects on protection and immune responses to rotavirus vaccines. Gnotobiotic pigs were injected intraperitoneally at birth with pooled serum from sows hyperimmunized with human rotavirus (HRV); control pigs received no sow serum. Pigs with or without MatAbs received either sequential attenuated HRV (AttHRV) oral priming and intranasal boosting with VP2/VP6 virus-like particle (VLP)-immunostimulating complex (ISCOM) (AttHRV/VLP) or intranasal VLP-ISCOM prime/boost (VLP) vaccines at 3 to 5 days of age. Subsets of pigs were challenged at 28 or 42 days postinoculation with virulent Wa HRV to assess protection. Isotype-specific antibody-secreting cell (ASC) responses to HRV were quantitated by enzyme-linked immunospot assay to measure effector and memory B-cell responses in intestinal and systemic lymphoid tissues pre- and/or postchallenge. Protection rates against HRV challenge (contributed by active immunity and passive circulating MatAbs) were consistently (but not significantly) lower in the MatAb-AttHRV/VLP groups than in the corresponding groups without MatAbs. Intestinal B-cell responses in the MatAb-AttHRV/VLP group were most suppressed with significantly reduced or no intestinal immunoglobulin A (IgA) and IgG effector and memory B-cell responses or antibody titers pre- and postchallenge. This suppression was not alleviated but was enhanced after extending vaccination/challenge from 28 to 42 days. In pigs vaccinated with nonreplicating VLP alone that failed to induce protection, MatAb effects differed, with intestinal and systemic IgG ASCs and prechallenge memory B cells suppressed but the low intestinal IgA and IgM ASC responses unaffected. Thus, we demonstrate that MatAbs differentially affect both replicating and nonreplicating HRV vaccines and suggest mechanisms of MatAb interference. This information should facilitate vaccine design to overcome MatAb suppression.

Animals↗

PubMed2005

Low titer maternal antibodies can both enhance and suppress B cell responses to a combined live attenuated human rotavirus and VLP-ISCOM vaccine.

We investigated effects of low titer (Lo) circulating MatAb on protection and immunogenicity of attenuated (Att) human rotavirus (HRV) priming and 2/6-virus-like particle (VLP)-immunostimulating complex (ISCOM) boosting (AttHRV/VLP) or VLP-ISCOM alone vaccines. LoMatAb had both enhancing and suppressing effects on B cell responses, depending on tissue, antibody isotype and vaccine. Differential effects of LoMatAb on IgA responses in different tissues suggest that LoMatAb did not suppress induction of IgA effector and memory B cells but impaired homing of these cells to secondary lymphoid or effector tissues, reducing IgA antibody secreting cells and antibodies at these sites. The AttHRV/VLP vaccine partially overcame LoMatAb suppression, conferred moderate protection against virulent HRV (as measured by reduced viral shedding and diarrhea) and represents a new candidate for rotavirus vaccines for both humans and animals.

Adjuvants, Immunologic↗

PubMed2005

The immunomodulating properties of human respiratory syncytial virus and immunostimulating complexes containing Quillaja saponin components QH-A, QH-C and ISCOPREP703.

A successful vaccine against human RSV (HRSV) is likely to induce a Th1 or a balanced Th1/TH2 cytokine response. We tested a panel of HRSV immunostimulating complexes (ISCOMs) containing different Quillaja saponin fractions (QH-A, QH-C, and 703: a mixture of 70% QH-A and 30% QH-C) with different immunological properties for their capacity of inducing innate and acquired immune responses. The HRSV 703 ISCOMs induced the strongest innate and acquired immune responses, followed by RSV QH-C and QH-A ISCOMs. All three formulations induced various degrees of Th1 bias response with prominent production of IFN-gamma being 10-50 times higher than that of IL-4 and IL-5. The HRSV specific IgG isotype profile correlated with the predominant secretion of Th1 cytokines, with strong induction of IgG2a antibodies. The 703 ISCOMs induced the most pronounced Th1 profile followed by QH-C and QH-A ISCOMs. The high incorporation of F protein in these ISCOMs compared to G protein combined with the Th1 biased nature of ISCOM are likely to be the causes to promote a Th1 type of profile. The prospect to formulate an RSV ISCOM formulation with an optimal Th1/Th2 balance is in reach particularly in view of the versatile properties of the ISCOM concept.

Adjuvants, Immunologic↗

PubMed2004

Bovine respiratory syncytial virus ISCOMs--protection in the presence of maternal antibodies.

The protection induced by immunostimulating complexes (ISCOMs) against bovine respiratory syncytial virus (BRSV) was evaluated and compared to that of a commercial inactivated vaccine (CV) in calves with BRSV-specific maternal antibodies. Following experimental challenge, controls (n = 4) and animals immunized with CV (n = 5) developed moderate to severe respiratory disease, whereas calves immunized with ISCOMs (n = 5) remained clinically healthy. BRSV was re-isolated from the nasopharynx of all controls and from all calves immunized with CV, but from none of the calves immunized with ISCOMs. BRSV-RNA was detected by real-time PCR from a single animal in this group. Significantly higher BRSV-specific nasal IgG, serum IgG1 and IgG2 titers were detected before and after challenge in animals immunized with ISCOMs versus CV. In conclusion, the ISCOMs overcame the suppressive effect of maternal antibodies in calves and induced strong clinical and virological protection against a BRSV challenge.

Adjuvants, Immunologic↗

PubMed2004

Current status and potential application of ISCOMs in veterinary medicine.

The immune stimulating complex (ISCOM) is a 40 nm nanoparticle used as a delivery system for vaccine antigens, targeting the immune system both after parenteral and mucosal administration. The ISCOM is made up of saponin, lipids and antigen usually held together by hydrophobic interaction between these three components. The compulsory elements to form the ISCOM structure are cholesterol and saponin. When the antigen is omitted the ISCOM-MATRIX is formed. There are a number of saponins that can form ISCOMs, and many other substances (including antigens, targeting and immuno-modulating molecules) can be incorporated into the ISCOM provided they are hydrophobic or rendered to be hydrophobic. Thus, it is possible to create ISCOM particles with different properties. After parenteral immunisation of the ISCOM, the T cell response is first detected in the draining lymph node. Subsequently, the T cell response is localised to the spleen, while the B cell response is first found both in the draining lymph nodes and in the spleen. Up to 50 days later, the majority of the antibody producing cells is found in the bone marrow (BM). In contrast, antigens that have been adjuvanted in an oil emulsion, limit the T cell response to the draining lymph nodes while the B cell response is found in the draining lymph nodes and spleen, but not in the BM. The ISCOM efficiently evokes CD8+, MHC class 1 restricted T cell response. The deposit of antigens both to the endosomal vesicles and to the cytosol of antigen presenting cells (APCs) explains why both T helper cells (vesicles) and cytotoxic T lymphocytes (cytosol) are efficiently induced by ISCOMs. The T helper (Th) cell response is balanced in the sense that both Th1 and Th2 cells are induced. Prominent IL-12 production by cells in the innate system is a characteristic reaction induced by ISCOMs, promoting the development of a strong Th1 response. After mucosal administration by the intranasal or the intestinal routes, the ISCOM induces strong specific mucosal IgA responses in local and remote mucosal surfaces. Also T cell responses are evoked by the mucosal administration. A large number of experimental ISCOM vaccines have been tested and protection has been induced against a number of pathogens in various species including chronic and persistent infections exemplified by human immune deficiency virus 1 (HIV-1), and 2 (HIV-2) and simian immune deficiency virus (SIV) in primates, and various herpes virus infections in several species. In contrast to a conventional rabies virus vaccine the ISCOM rabies formulation protected mice after exposure to the virulent virus. Recently, experimental ISCOM vaccines were shown to efficiently induce immune response in newborns of murine and bovine species in the presence of maternal antibodies, while conventional vaccines have failed. ISCOM vaccines are on the market for horses and cattle and several other ISCOM vaccines are under development. Since the ISCOM and the ISCOM-MATRIX can be blended with live attenuated vaccine antigens without hampering the proliferation of the live vaccine antigens, it opens the possibility to use the ISCOM adjuvant system in a mixture of live and killed vaccine antigens.

Animal Diseases↗

PubMed2004

Neutralization of primary HIV-1 SF13 can be detected in extended incubation phase assays with sera from monkeys immunized with recombinant HIV-1 SF2 gp120.

Phase III efficacy trials of recombinant human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins were postponed. In Phase I and II trials these candidate vaccines had failed to induce neutralizing antibodies against virus which had been isolated by co-culture with human peripheral blood mononuclear cells (PBMC). The aim of the present study was to determine assay conditions for detecting neutralization of primary HIV-1 isolates with sera from immunized individuals. We show that in two immunogenicity trials in rhesus macaques, recombinant HIV-1 SF2 gp120 induced antibodies which neutralized the primary HIV-1 SF13 isolate. Statistically significant in vitro neutralization required assays in which the incubation phase was extended. Sterile immunity was only seen with the highest level of neutralization, induced by a recombinant prime, peptide boost strategy. We recommend that neutralization assays with extended incubation phases should be used to monitor Phase III efficacy trials.

AIDS Vaccines↗

PubMed2004

Safety and efficacy of immune-stimulating complex-based antigen delivery systems for neonatal immunisation against respiratory syncytial virus infection.

To protect against human respiratory syncytial virus (hRSV)-induced bronchiolitis in early infancy, vaccines need to be designed which are effective in the neonatal period. To test the safety and efficacy of adjuvants in neonatal mice, we injected hRSV surface proteins combined with immune-stimulating complexes (ISCOMs) prepared from fractions A, C or A + C of Quillaja saponins. All were well tolerated in adults, but A + C ISCOMS proved lethal in neonates; A or C fractions alone were well tolerated by neonates up to the adult dose. hRSV-ISCOM A induced antibody responses similar to combined fractions, and potent in vitro cytotoxic T cell responses. Adult-like in vitro cytotoxicity against hRSV-infected targets and precursor cytotoxic T cell frequencies were observed within one week of neonatal priming and hRSV-ISCOM A-primed neonates showed virtually complete protection against subsequent viral challenge. hRSV challenge was associated with some pulmonary eosinophilia in both age groups, with higher IL-4 production by lung CD4+ T cells in mice primed as neonates. This was, however, accompanied by only minor (approximately 10%) and transient illness and weight loss. Thus, the identification of hRSV antigen delivery systems with an age-appropriate adjuvanticity/reactogenicity balance may be feasible even in the vulnerable early-life period.

Adjuvants, Immunologic↗

PubMed2003

Influence of maternal immunity on antibody and T-cell response in mice.

The prevalence of maternal antibodies (Abs) and an immature neonate immune system, which is inclined to a T-helper 2 (Th2) response, are factors that counteract active immunization in early life. In a mouse model, the maternal influence on an active immunization of 2-day-old offspring with Sendai virus (SV) envelope proteins was explored. Maternal immunizations were conducted with the same SV antigen preparation as used for offspring immunization, presented in three different formulations, namely micelles of SV (SV-MIC), Al(OH)(3)-adjuvanted SV-MIC (SV-aluMIC) for Th2 and immune stimulation complex (iscom)-adjuvanted SV (SV-ISC) for Th1. An inversely correlation was found between the immunoglobulin G2a (IgG2a) Abs of the mothers and the interleukin 5 (IL-5) levels of the offspring. Although a maternally derived immunity induced by SV-aluMIC suppressed both B- and T-cell responses of the newborn to SV-ISC immunization, significant priming effects of the neonatal immunization on IgG2a Abs and IFN-gamma levels were recorded after reimmunization at adult age.

Animals↗

PubMed2002

Vaccination with recombinant alphavirus or immune-stimulating complex antigen against respiratory syncytial virus.

Respiratory syncytial virus (RSV) causes severe respiratory diseases in infants and young children. Inappropriate immunity to the virus can lead to disease enhancement upon subsequent infection. In this study, we have characterized the antiviral immunity elicited by the recombinant Semliki Forest virus (SFV) encoding the RSV fusion (F) and attachment (G) protein, and compared with that induced by the immune-stimulating complex (ISCOM)-incorporated FG proteins. Antiviral immunity against RSV elicited nasally or parentally by either of the immunogen having divergent profiles could reduce lung RSV titers upon challenge. However, resistance to RSV without disease enhancement was only observed in those vaccinated with SFV recombinants via nasal route. Presence of postvaccination pulmonary IFN-gamma response to the H-2K(d)-restricted T cell epitope (F(85-93); KYKNAVTEL) was found to be associated with absence of enhanced pulmonary disease and goblet cell hyperplasia as well as reduced Th2-cytokine expression. This result demonstrates that the SFV recombinants can result in enhanced clearance of RSV without enhancing the RSV-associated disease, and underlines the importance in priming pulmonary MHC class I-restricted T cells when RSV FG-based vaccines are used.

Administration, Intranasal↗

PubMed2002

Immunity in neonates.

Passively derived maternal immunity hampers active immunization of newborns. Further, an immature immune system contributes to a weak and Th2 polarized immunity. This state of immunity in early life sustains endemic infections in man and continuous reinfections in animal herds. The endemic infections of the young occur preferentially when the immune system is still functionally immature and when the low levels of maternal antibodies are no longer protective but yet blocks protective immune responses. Vaccines overcoming these problems would have strong positive effects on the herd health and environmental benefits. The Th2 bias of the newborn is mediated by high levels of progesterone and Th2 cytokines produced in the maternal-fetal interface. The activity of the innate system is enhanced in the mother during the prepartus period, certainly having effects on the offspring. Newborn, 2-days-old, mice can be primed with Sendai virus envelope proteins as model antigens to induce Th1 or Th2 responses, dependent on the supplementation of the virus antigen formulation with Th1 or Th2 adjuvants. This priming has a strong life-long effect when complemented with subsequent boosts. However and importantly this priming effect can be modulated by adjuvants focusing for Th1 and Th2 when applied to the mice at 6 weeks of age, i.e. when they are immunologically adult. It has been shown in various species, besides mice, i.e. dog, sheep, horse and seal, that a strong Th1 driving adjuvant can induce immune response and protection in newborns when conventional vaccines fail. In conclusion, the Th2 bias prevailing around partus can be overcome by appropriate immunological treatments, permitting effective vaccination and protective immunity in the newborn.

Adjuvants, Immunologic↗

PubMed2002

Systemic and intestinal antibody secreting cell responses and protection in gnotobiotic pigs immunized orally with attenuated Wa human rotavirus and Wa 2/6-rotavirus-like-particles associated with immunostimulating complexes.

The undesirable side effects and variable efficacy of some oral live rotavirus vaccines in infants have necessitated alternative vaccine approaches. We evaluated a recombinant RFVP2/WaVP6 rotavirus-like-particle (2/6VLP) oral vaccine, using an immunostimulating complex (ISCOM) matrix as adjuvant, in a gnotobiotic (Gn) pig model of human rotavirus (HRV) disease. The 2/6VLPs adhered to the ISCOM-matrix (2/6VLP-ISCOM ) and were antigenic, but they failed to induce protection. However, when combined with attenuated (Att) HRV for oral priming, the 2/6VLP-ISCOM vaccine was effective as a booster and induced partial protection against virulent Wa HRV. The 250 microg 2/6VLP dose was more effective than 100 microg. The highest mean numbers of IgA antibody secreting cells evaluated by ELISPOT in intestinal lymphoid tissues were in pigs receiving AttHRV+2/6VLP-ISCOM or three doses of AttHRV and were associated with the highest protection rates.

Administration, Oral↗

PubMed2002

Transmission pattern of parainfluenza 3 virus in guinea pig breeding herds.

In searching for the cause of experimental variations in respiratory research data, serology revealed the prevalence of antibodies against parainfluenza virus type 3 (PIV 3) in guinea pigs. The aim of the present study was to explore the transmission rate, course, and kinetics of enzootic PIV 3 infection in guinea pig breeding units. In the first part of the study, blood samples to be analyzed for PIV 3 antibodies were collected from guinea pigs of a PIV 3-positive breeding colony at different times after birth. In the same breeding unit, 6 of 12 2-week-old guinea pigs were relocated and separately housed. The PIV 3 serum antibody titers of the two groups were compared at various times from birth to 13 weeks after birth. In the second part of the study, the spread of infectious virus and virus persistence were explored by housing seronegative sentinel animals together with 2- to 3-week-old guinea pigs from three different PIV 3-positive breeding units. The guinea pigs remaining in the breeding colony as well as those removed and housed separately showed declining serum antibody titers for about 1 month after birth, thereafter the titers were stable until about 8 weeks after birth. Five weeks later, the mean antibody titer of the guinea pigs remaining in the breeding colony had increased to a markedly higher level than that of the relocated, separately housed guinea pigs. Seroconversion was demonstrated in 7 of the 14 sentinels housed with the 2- to 3-week-old guinea pigs from PIV 3-positive breeding units. Sentinels housed together with PIV 3-positive guinea pigs 24 weeks after the start of the experiment did not seroconvert. We conclude that young guinea pigs born to PIV 3-positive mothers were protected by maternal immunity against infection with PIV 3 during their first 14 days of life. The guinea pig offspring became infected during the period from about 2 weeks until 8 weeks after birth, as demonstrated by seroconversion of sentinel animals and an increasing mean antibody titer seen beyond 8 weeks of age. The study did not reveal any indication of virus persistence or prolonged carrier status.

Animal Husbandry↗