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P A Offit

Publications and source records attributed to P A Offit.

At least 37 records · Page 2Linked to original sources
PubMed1996

WC3 reassortant vaccines in children.

Bovine rotavirus strain WC3 (P7[5], G6) administered at the 12th passage level was well tolerated clinically in infants and efficiently induced serum virus neutralizing antibody (VNA) with bovine rotavirus G6 specificity. The protective efficacy of WC3 vaccine against all rotavirus disease was inconsistent, varying in four separate trials from 76% to 0%; some selective protection against severe disease was seen in all trials. WC3 reassortants containing the gene for an individual human rotavirus VP7 (G) or VP4 (P) surface antigen were also well tolerated, but preferentially induced VNA to the WC3 parent. Efficacy trials of human G1 VP7 reassortant WI79-9 (P7[5], G1) consistently led to > 60% protection against all rotavirus disease. A quadrivalent WC3 reassortant vaccine was developed to contain four separate monovalent reassortants expressing human rotaviruses surface proteins G1, G2, G3, and P1A [8] respectively. In a multicenter trial including 439 infants, this vaccine induced 67.1% protection against all rotavirus disease (defined as positive for rotavirus antigen by ELISA only [p = < 0.001]) and 72.6% protection when the standard for rotavirus diagnosis was a positive test of stool for both rotavirus antigen by ELISA and rotavirus RNA by electropherotype analysis (p = < 0.001). In this trial, episodes of the most severe rotavirus disease (clinical severity score > 16.0 eight cases) occurred only in placebo recipients.

Animals↗
PubMed1996

Aqueous-based microencapsulation enhances virus-specific humoral immune responses in mice after parenteral inoculation.

Vaccines are commonly administered by the parenteral route. Therefore, adjuvant strategies which include parenteral immunization may improve the efficacy of a number of current vaccines. The capacity of aqueous-based microencapsulation to enhance virus-specific IgG responses in mice inoculated intramuscularly with small quantities of antigen was evaluated. Mice were inoculated with either 10(4), 10(3), or 10(2) p.f.u. of microencapsulated rotavirus (bovine strain WC3), placebo microcapsules plus free virus, or virus alone. Mice were subsequently bled 1, 2, 4, 6, and 9 months after inoculation. Microencapsulation of rotavirus enhanced virus-specific humoral immune responses. In addition, virus-containing microcapsules composed of spermine-chondroitin sulfate induced levels of virus-specific antibodies greater than those found after inoculation with virus-containing microcapsules composed of spermine-alginate. Mechanisms by which microencapsulation may enhance virus-specific humoral immunity are discussed.

Animals↗
PubMed1996

Host factors associated with protection against rotavirus disease: the skies are clearing.

Over the past several years, a number of studies have clarified aspects of rotavirus immunology and vaccinology previously considered controversial. In this review, studies that address the following questions will be summarized: Which host factors are responsible for recovery from acute rotavirus infection? Are the host factors responsible for recovery from acute infection the same as those necessary for prevention of infection? What is the relative importance of the nature of the inoculum (e.g., homologous or heterologous host virus and live or inactivated virus), route of inoculation, or virus serotype in vaccine development? What is the immunologic basis by which infection with 1 viral serotype protects against challenge with another serotype (heterotypic protection)?

Animals↗
PubMed1996

The development of multivalent bovine rotavirus (strain WC3) reassortant vaccine for infants.

Laboratory and clinical studies have been directed toward development of a vaccine against rotavirus gastroenteritis in infants. First, bovine rotavirus strain WC3, which did not induce neutralizing antibodies to predominant human rotavirus (HRV) serotypes, was determined to be safe and immunogenic; however, it was not protective in all efficacy trials. HRVs adapted to cell culture retained some virulence for infants, but when further attenuated by cold adaptation, they were poorly immunogenic. Reassortant rotaviruses were designed to express HRV surface proteins VP7 (G) or VP4 (P) while retaining a bovine WC3 genome background. Reassortants containing either HRV surface protein and as few as four bovine rotavirus genes were safe in infants. A monovalent WC3 reassortant of serotype G1 specificity was 64%-100% protective in placebo-controlled trials. A quadrivalent WC3 reassortant vaccine with components of HRV G1, G2, G3, and P[8] specificity induced 67% protection against all rotavirus disease in a multicenter efficacy trial.

Animals↗
PubMed1995

Enhancement by microencapsulation of rotavirus-specific intestinal immune responses in mice assessed by enzyme-linked immunospot assay and intestinal fragment culture.

The capacity of microencapsulation to enhance the humoral immune response to rotavirus in the gut-associated lymphoid tissue (GALT) of mice was determined by using a system of microencapsulation based on the ionic linkage of aqueous anionic polymers and an aqueous amine. Inoculation of mice with microencapsulated rotavirus enhanced the frequencies of virus-specific IgA-secreting cells in the lamina propria as well as the quantities of virus-specific IgA produced in GALT. In addition, an enhanced virus-specific immune response was associated with enhanced production of presumably polyclonal, non-rotavirus-specific antibodies in GALT. The mechanism by which microencapsulation enhances the humoral immune response remains to be determined.

Alginates↗
PubMed1995

Oral inoculation of mice with low doses of microencapsulated, noninfectious rotavirus induces virus-specific antibodies in gut-associated lymphoid tissue.

The capacity of an aqueous-based system of microencapsulation to enhance virus-specific humoral immune responses was evaluated in mice orally inoculated with noninfectious rotavirus (simian rotavirus strain RRV). Mice were orally inoculated with 1.75 or 0.35 microgram of inactivated RRV (iRRV) or microencapsulated iRRV. Sera, intestinal contents, and organ cultures of gut-associated lymphoid tissues (GALT) were tested for the presence of rotavirus-specific antibodies. Virus-specific IgA was produced by small intestine lamina propria lymphocytes in animals inoculated with 1.75 or 0.35 microgram of microencapsulated virus, but not in mice inoculated with unencapsulated virus. Virus-specific IgA in sera and intestinal contents were not predictive of intestinal organ culture responses. Microencapsulation may be an efficient way of inducing virus-specific immune responses in GALT after oral inoculation with small quantities of viral antigen. In addition, delayed release of virus from microcapsules may obviate the need for booster immunizations.

Administration, Oral↗
PubMed1995

Induction of virus-specific antibody production by lamina propria lymphocytes following intramuscular inoculation with rotavirus.

The relative capacities of intramuscular (im) or oral inoculation of mice with live or inactivated rotavirus to induce a virus-specific humoral immune response in gut-associated lymphoid tissues (GALT) was evaluated. At 4-5 weeks after oral inoculation with live virus, virus-specific IgA was detectable in serum, intestinal contents, and GALT organ culture. Five weeks after im inoculation with live or inactivated virus, virus-specific IgA was detected in GALT organ culture at levels approximately 10-fold less than those found after oral inoculation with live virus. Therefore, neither replication of virus in small intestinal epithelial cells nor presentation of virus at the intestinal mucosal surface was necessary for the induction of virus-specific antibodies by GALT. Possible mechanisms by which im inoculation of virus induces production of virus-specific antibodies by GALT are discussed.

Animals↗
PubMed1994

Enhancement of rotavirus immunogenicity by microencapsulation.

It was determined whether microencapsulation of rotavirus enhanced virus-specific immunity in mice. Combinations of several water-soluble anionic polymers and amines were tested for their capacity to form microcapsules which were stable in the presence of simulated gastric acid. Using the combinations of sodium alginate and spermine hydrochloride or sodium chondroitin sulfate and spermine hydrochloride we found that microcapsules (1) captured infectious rotavirus, (2) penetrated into the persisted in gut-associated lymphoid tissue (GALT) after oral inoculation, (3) delivered rotavirus antigen to GALT at levels greater than those detected after oral inoculation with free virus, and (4) enhanced the virus-specific humoral immune response after oral or parenteral immunization.

Amines↗
PubMed1994

Induction of rotavirus-specific cytotoxic T lymphocytes by vaccinia virus recombinants expressing individual rotavirus genes.

We determined the capacity of vaccinia virus recombinants expressing individual rotavirus genes to induce virus-specific cytotoxic T lymphocytes (CTLs) in mice. Mice were orally inoculated with vaccinia virus recombinants containing genes which encode rotavirus outer capsid proteins vp4 or vp7, single-shelled virus proteins vp1, vp2, or vp6, or rotavirus nonstructural proteins NS53, NS35, NS28, or NS26/NS12. We found that (i) the greatest frequencies of virus-specific CTLs were induced by vaccinia virus recombinants expressing vp7, (ii) transport of vp7 beyond the endoplasmic reticulum was not necessary for induction of CTLs, (iii) recombinants expressing vp7 induced CTLs which reacted with different rotavirus serotypes, and (iv) CTLs were induced among both intestinal and nonintestinal lymphocytes after oral inoculation. These findings may be relevant to vaccine strategies which utilize vectors expressing individual rotavirus genes.

Administration, Oral↗
PubMed1994

Rotaviruses: immunological determinants of protection against infection and disease.

Although studies of rotavirus immunity in experimental animals and humans have often yielded conflicting data, a preponderance of evidence supports the following answers to the questions initially posed. 1. What is the importance of virus serotype in formulating an optimal vaccine? Both vp4 and vp7 induce virus-neutralizing antibodies after either natural infection or immunization; the capacity of vp4 to induce rotavirus-specific neutralizing antibodies is probably greater than that of vp7. However, protection against disease after immunization of infants and young children is induced by strains heterotypic to the challenge virus (e.g., immunization with WC3 induces protection against disease induced by serotypically distinct human G1 strains). In addition, oral inoculation of infants with primate or bovine reassortant rotaviruses containing genes that encode human vp7 has not consistently induced a higher level of protection against challenge than that induced by parent animal rotaviruses (see Table I). Therefore, although vp4 or vp7 or both are probably important in inducing protection against challenge, it has not been clearly demonstrated that inclusion of the epidemiologically important human (as distinct from animal) P or G type is important in protection against human disease. 2. Which immunological effector arm most likely protects against rotavirus disease? No immunological effector arm clearly explains protection against heterotypic challenge. Protection against disease is not predicted by rotavirus-specific neutralizing antibodies in serum. Rotavirus-specific, binding sIgA in feces [detected by enzyme-linked immunosorbent assay (ELISA)] induced after natural infection does correlate with protection against disease induced by subsequent infection. However, protection after immunization with WC3 may occur in the absence of a detectable fecal sIgA response. The relationship between rotavirus-binding sIgA and sIgA-mediated neutralizing activity directed against the challenge virus remains to be determined. Binding rotavirus-specific sIgA in feces detected by ELISA may only be a correlate of other events occurring at the intestinal mucosal surface. The presence of broadly cross-reactive, rotavirus-specific CTLs at the intestinal mucosal surface of mice acutely after infection is intriguing. It would be of interest to determine the degree to which the presence of cross-reactive, rotavirus-specific CTLs in the circulation is predictive of the presence of virus-specific CTLs among intestinal lymphocytes and protection against challenge. Unfortunately, studies of virus-specific CTLs are difficult to perform in children. 3. By what means is virus antigen best presented to the host to elicit a protective immune response? Oral inoculation may not be necessary to induce a protective, virus-specific immune response at the intestinal mucosal surface.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Rotavirus-specific intestinal immune response in mice assessed by enzyme-linked immunospot assay and intestinal fragment culture.

Primate rotavirus strain RRV and bovine strain WC3 or reassortants made between these animal viruses and human rotaviruses have been administered to infants as candidate vaccines. We compared RRV and WC3 in a murine model of oral infection. We determined the relative capacities of these viruses to induce a virus-specific humoral immune response by intestinal lymphocytes as tested by enzyme-linked immunospot assay, intestinal fragment culture, and enzyme-linked immunosorbent assay of intestinal contents. We found that inoculation of mice with RRV induced higher frequencies of virus-specific immunoglobulin A (IgA)-secreting cells in the lamina propria, greater quantities of virus-specific IgA in intestinal fragment cultures, and greater quantities of virus-specific IgA in intestinal secretions than did inoculation with WC3 or inactivated RRV (iRRV). The induction of an IgA response in serum was predictive of an IgA response among intestinal lymphocytes after inoculation with RRV but not WC3. In addition, large quantities of IgG, IgA, and IgM not specific for rotavirus were produced in fragment cultures from mice inoculated with RRV but not in cultures from mice inoculated with WC3 or iRRV. Possible mechanisms of RRV-induced polyclonal stimulation of intestinal B cells are discussed.

Animals↗
PubMed1993

Rotavirus-specific humoral and cellular immune response after primary, symptomatic infection.

The humoral and cellular immune response after symptomatic, primary rotavirus infection was examined in 8 children < 2 years old. Rotavirus-specific IgA, rotavirus-specific helper T (Th) cells, and neutralizing antibody responses were evaluated at the time of illness, 2-8 weeks later, and 3-5 months later. In addition, rotavirus strains associated with infection were tested by polymerase chain reaction analysis using oligonucleotide primers specific for genes 4 (P type) and 9 (G type). The absence of rotavirus-specific IgA or rotavirus-specific helper T cell activity at the time of illness was consistent with a primary infection in 7 of 8 children. Two children were infected with serotype 1 (P type 1, G type 1), 3 with serotype 3 (P type 1, G type 3), and 3 with serotype 4 (P type 1, G type 4) strains. Neutralizing antibodies were directed against the gene 4 (P type) protein product (vp4). Because all infecting strains were P type 1, convalescent antisera did not distinguish among different rotavirus G types. Rotavirus-specific IgA responses were detected in 6 of 8 and rotavirus-specific Th cell responses in 7 of 8 children during convalescence.

Acute Disease↗
PubMed1992

Rotavirus-specific helper T cell responses in newborns, infants, children, and adults.

An obstacle to developing a successful rotavirus vaccine has been the inability to consistently correlate the humoral immune response with protection against disease. Transplacental transfer of maternal rotavirus-specific antibodies may obscure the capacity to discriminate an active from a passively acquired humoral immune response in infants. In an attempt to circumvent this problem, an assay was developed to detect rotavirus-specific helper T cells among circulating mononuclear cells. Rotavirus-specific lymphoproliferative responses and rotavirus-specific neutralizing antibody titers in blood were determined in 11 mother/newborn pairs at the time of delivery and in 54 infants, children, and adults ranging in age from 16 days to 40 years. Only 1 of 11 infants tested between 16 days and 6 months of age had detectable rotavirus-specific helper T cell activity whereas 8 of 11 had circulating rotavirus-specific neutralizing antibodies. Acquisition of rotavirus-specific helper T cell activity over the first few years of life correlated with the age at which infants and young children are known to be infected with rotavirus. These findings support the hypothesis that detection of rotavirus-specific lymphoproliferative activity in infants may more accurately determine previous exposure to rotavirus than detection of rotavirus-specific antibodies.

Adolescent↗
PubMed1991

Outer capsid glycoprotein vp7 is recognized by cross-reactive, rotavirus-specific, cytotoxic T lymphocytes.

Cytotoxic T lymphocytes (CTLs) generated in mice orally inoculated with rotaviruses lyse target cells infected with different rotavirus serotypes (cross-reactive CTLs). Using vaccinia virus recombinants expressing individual rotavirus proteins from two different rotavirus serotypes, we found that cross-reactive CTLs recognize target cells expressing outer capsid protein vp7 better than those expressing outer capsid protein vp4 or inner capsid protein vp6. These findings may be relevant to vaccine strategies which include immunization with reassortant rotaviruses or viral or bacterial vectors expressing individual rotavirus proteins. The region or regions of vp7 which are antigenically conserved among different rotavirus serotypes and recognized by cross-reactive CTLs remain to be determined.

Animals↗