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Biomedical subjects

Robert M Jacobson

Publications and source records attributed to Robert M Jacobson.

At least 37 records · Page 2Linked to original sources

A reexamination of the feasibility of the administration of routine childhood vaccines in emergency departments in the era of electronic vaccine registries.

OBJECTIVES: To determine if electronic vaccine records facilitate successful routine childhood vaccination in the emergency department (ED). METHODS: We sampled consecutively over 2 calendar months children younger than 24 months presenting to the ED. Parents and legal guardians of eligible children were offered enrollment. Those consenting completed a parental survey after a nurse conducted an initial assessment of eligibility. Attending physicians then completed the assessment, and after the visit, the electronic vaccination records, when available, were accessed. No actual routine childhood vaccines were given during the study. RESULTS: Three hundred thirty-four were approached: 17 (5.1%) declined participation; 10 (3.0%) were enrolled, but the data were lost, and 7 (2.1%) were excluded. Of the 300 remaining, 235 (78.3%) had available electronic vaccine records. Only 38 (16.2%) of the 235 were late for at least 1 vaccine. Of note, physicians assessed 22 (57.9%) of the 38 as medically appropriate for vaccination in the ED. The overwhelming majority (81.8%) of the 22 parents and guardians would have assented to vaccination in the ED. Of the 38 patients found late for vaccination, 31 (81.6%) of parents incorrectly reported their children to be up-to-date on their immunizations. CONCLUSIONS: Assuming that the electronic vaccination record performed such as an online vaccine registry, the effort to access the registry might find a substantial number of children late for a routine childhood vaccination. In this setting, we found that approximately one sixth of the children with electronic vaccine records would be found late for vaccination, and based on physician assessment and parental survey, one half of those children would receive that vaccination if available in the ED. These rates offer health care planners a sense of the magnitude of the vaccination rates in the ED as we move toward regional vaccination registries with online capabilities to be accessed by EDs.

Emergency Service, Hospital↗

A parent-driven, computer-based vaccine information system: addressing variability in information needs for the varicella vaccine.

OBJECTIVE: To determine the variability of parental interest in the depth of detail provided regarding vaccine information. PARTICIPANTS AND METHODS: We performed a cross-sectional, observational study in a primary care pediatric practice from September 1 to September 30, 1995. We provided each participant an opportunity to use a self-directed, computer-based information system using the varicella vaccine as a prototype. The system covered 7 topics regarding the vaccine and offered 5 stages of information, ranging from general, indisputable information at stage 1 to less common, potentially unresolved details at stage 5. Parents viewed stage 1 information for each topic. Parents would then choose to either view more stages or view the next topic. RESULTS: Of 130 parents visiting the pediatric practice, 112 (86%) agreed to participate. We found substantial variability in the amount of information sought. Some parents stopped with stage 1 information (15%-45%, depending on the topic), whereas others indicated they would seek more information beyond the fifth stage (2%-14%). Overall, parents reported high satisfaction with the system. CONCLUSION: Quantifiable variability exists in parents' requirements for vaccine information, and our information system addresses this issue.

Adult↗

Immunogenicity and reactogenicity of a novel vaccine for human papillomavirus 16: a 2-year randomized controlled clinical trial.

OBJECTIVE: To evaluate the immunogenicity, reactogenicity, and tolerability of a prototype human papillomavirus (HPV) 16 viruslike particle (VLP) vaccine directed against the L1 capsid protein. SUBJECTS AND METHODS: We enrolled healthy nonpregnant women aged 18 to 26 years into a 2-year, double-blind, dose-ranging multicenter trial (October 12, 1998, to September 30, 2001). Subjects were assigned to study groups to receive a 3-dose regimen (day 0, month 2, and month 6) of 1 of 4 vaccine doses: 10 microg, 20 microg, 40 microg, or 80 microg or placebo. Serum anti-HPV 16 L1 antibody (sL1Ab) geometric mean titers (GMTs) were measured at day 0, at month 3, at month 7, and every 6 months for a total of 2 years using a radioimmunoassay. The primary immunogenicity analyses evaluated GMTs at month 7 in L1Ab-seronegative subjects at baseline. Vaccine tolerability was also assessed. RESULTS: A total of 480 subjects were randomized to receive placebo (n=52) or 10 microg (n=112), 20 microg (n=105), 40 microg (n=104), or 80 microg (n=107) of HPV 16 L1 VLP vaccine. At baseline, 75% of subjects were L1Ab seronegative. All vaccine doses produced a statistically significant sL1Ab response vs placebo (P<.001). At the completion of the vaccination regimen, sL1Ab GMTs in baseline-seronegative subjects were 36- to 78-fold higher than the sL1Ab GMT at day 0 observed in subjects who had mounted an immune response to HPV 16 infection before enrollment. Serum L1Ab GMTs remained high throughout the 1.5-year postvaccination period. Postvaccination sL1Ab GMTs were 1.1- to 2.4-fold higher in women who had detectable sL1Ab levels at enrollment compared with those in baseline-seronegative subjects, particularly in the persistence phase. The vaccine was generally well tolerated with no statistically significant differences in injection site or systemic adverse experiences among treatment groups. CONCLUSION: Immunization with this novel HPV 16 L1 VLP vaccine was well tolerated and produced an immunogenic response that persisted for at least 1.5 years after the final dose.

Adolescent↗

Associations between human leukocyte antigen (HLA) alleles and very high levels of measles antibody following vaccination.

Associations between human leukocyte antigen (HLA) genes and very high levels of antibodies (or hyperseroresponsiveness) to measles antigens in a genetically heterogeneous human population are poorly understood. We studied the association between antibody levels after measles vaccination and HLA class I and II alleles among 170 US schoolchildren who received one dose of measles-mumps-rubella II vaccine. Vaccine recipients were divided into two groups: 93 recipients who were seropositive and 77 recipients who were hyperseropositive (the upper 10th percentile of antibody levels of all subjects). Out of all the alleles analyzed, HLA-B(*)7 (odds ratio (OR) 1.9; P = 0.05), DQA1(*)0104 (OR 4.6; P = 0.02) and DPA1(*)0202 (OR 4.8; P = 0.04) alleles were positively associated with hyperseropositivity, whereas HLA-B(*)44 (OR 0.4; P = 0.02), DRB1(*)01 (OR 0.6; P = 0.09), DRB1(*)08 (OR 0.3; P = 0.04), DQB1(*)0301 (OR 0.5; P = 0.04), and DPB1(*)0401 (OR 0.6; P = 0.03) alleles were negatively associated with hyperseropositivity. The alleles B(*)44, DRB1(*)01, DRB1(*)08 and DQA1(*)0104 remained statistically significant after accounting for the effects of other alleles. The results suggest that HLA alleles have important associations with measles antibody hyperseropositivity. These data increase our understanding of measles vaccine-induced immune response and will be useful for future mechanistic work on measles virus antigen processing and presentation in seronegative and hyperseropositive individuals.

Alleles↗

The contribution of HLA class I antigens in immune status following two doses of rubella vaccination.

The variability of humoral and cellular immune responses modulated by human leukocyte antigen (HLA) genes is a significant factor in the protective effect of rubella vaccines. We performed HLA class I typing in a group of 346 healthy schoolchildren and young adults who previously received two doses of measles-mumps-rubella-II vaccine. Rubella virus-specific humoral (serum antibody) immunity and cell-mediated immunity (lymphocyte proliferation) were assessed. Median values for antibody levels and stimulation indices (SI) were 38.63 IU/ml and 2.29 IU/ml, respectively. The alleles that provided suggestive, but not conclusive, evidence of HLA association with rubella seropositivity were HLA-B*2705 (median, 24.68 IU/ml; p = 0.160), B*4501 (median, 61.22 IU/ml; p = 0.098), Cw*0303 (median, 30.34 IU/ml; p = 0.102) and Cw*0704 (median, 26.58 IU/ml; p = 0.144). These alleles approach, but do not achieve, statistical significance. Of all the alleles analyzed, HLA-B*3503 (median SI, 3.00; p = 0.031) and HLA-Cw*1502 (median SI, 3.19; p = 0.035) were positively associated with lymphoproliferative responses to rubella virus antigens, whereas the HLA-B*3901 (SI, 1.34; p = 0.066) allele was negatively associated. This suggests that class I HLA alleles may have limited associations with humoral and cellular immune responses to rubella vaccine. These data may facilitate our understanding of immune response variation in a genetically outbred heterogeneous population.

Adolescent↗

Interleukin-4 induced by measles virus and measles-derived peptides as measured by IL-4 receptor-blocking ELISA.

Interleukin-4 (IL-4) is a signature cytokine for T-helper 2 (Th2) type immune responses in humans. However, data on antigen-specific secretion of IL-4 is limited due to difficulties detecting IL-4. We evaluated an IL-4 receptor-blocking assay for the detection of secreted IL-4 in peripheral blood mononuclear cells (PBMC) stimulated in vitro with measles virus (MV) and MV-derived nucleoprotein (N) and phosphoprotein (P) peptides. We recruited 20 healthy subjects, previously immunized with two doses of measles-mumps-rubella-II (MMR-II) vaccine. We evaluated the cellular and humoral immune status of these study subjects by an in vitro lymphoproliferation assay and an enzyme-linked immunosorbent assay (ELISA), respectively. We analyzed the MV-induced and N and P peptide-induced IL-4 levels in PBMC culture supernatants. Using the IL-4 receptor blocking assay, 50% of the subjects were positive for secreted IL-4 in response to MV stimulation, and 5% and 23.1% of study subjects were positive for secreted IL-4 in response to MV-derived N and P peptides, respectively. In contrast, we did not find any positive secreted IL-4 response to MV using conventional ELISA without IL-4 receptor-blocking antibody in our optimization study. Further, we found very low frequencies of IL-4 secreting cells using an alternate ELISpot technique, accounting for only a 5% positive response to MV and no response to P peptide. We propose that the IL-4 receptor-blocking assay is an easy-to-adapt technique for screening antigen-specific immune responses in large-scale population-based studies.

Adolescent↗

Pertussis vaccination and the risk of respiratory syncytial virus-associated hospitalization.

BACKGROUND: Animal data suggest an association between recent vaccination with a pertussis-containing vaccine and increased severity of respiratory syncytial virus (RSV) infection. We sought to determine whether such an association exists in humans by studying a population-based cohort of young children. PATIENTS AND METHODS: We performed a nested case-control study of 280 children younger than 24 months of age hospitalized with RSV infection in Olmsted County, MN from January 1990 to December 1999. Controls (2 per case) consisted of nonhospitalized residents of Olmsted County matched to cases by date of birth and sex. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for the odds of hospitalization for RSV infection among subjects with a recent pertussis-containing vaccination in proximity to the cases' date of hospitalization relative to the odds among subjects with no vaccination. RESULTS: The OR for receipt of a pertussis-containing vaccine within 0 to 6 days of a case's hospitalization for RSV disease was 0.8 (95% CI 0.4-1.8). For the time intervals 7-13, 14-20 and > or =21 days, the OR were 1.3 (95% CI 0.5-3.0), 1.3 (95% CI 0.5-3.2) and 0.7 (95% CI 0.3-1.5), respectively. Adjusting for vaccine delay and for risk status did not alter the findings. The median interval between the most recent pertussis-containing vaccine and the case's date of hospitalization was 40 days for cases and 42.5 days for controls (P = 0.69). Among the RSV cases, pertussis vaccination in the month preceding hospitalization was not a risk factor for oxygen requirement (P = 0.82), intensive care unit admission (P = 0.46) or need for mechanical ventilation (P = 0.28). CONCLUSION: In our study, recent immunization with a pertussis-containing vaccine was not a risk factor for hospitalization for RSV infection. In addition, among children hospitalized with RSV infection, recent pertussis immunization was not associated with a more severe clinical course.

Case-Control Studies↗

Variation in vaccine response in normal populations.

Genetic polymorphisms of the human leukocyte antigen (HLA) system significantly influence the variation in immune responses to viral vaccines. Considerable data on the genetic determinants of immune responses to the measles vaccine support the importance of HLA genes in determining the variation in vaccine response. HLA class I and class II, TAP, and HLA-DM allele associations with measles-specific antibody levels following measles vaccination have revealed, in part, the immunologic basis for mechanisms of measles immunity variation. Associations between HLA genotype and immune responses have also been reported for other vaccines and infectious diseases, such as hepatitis B and C, human papillomaviruses, and influenza. Vaccine pharmacogenomics may provide important insights for the design and development of new peptide-based vaccines against measles and other pathogens.

Genetic Variation↗

Hepatitis B DNA vaccine induces protective antibody responses in human non-responders to conventional vaccination.

A novel DNA vaccine against hepatitis B virus was administered intraepidermally by particle-mediated epidermal delivery (PMED) to 16 human subjects who demonstrated absent or non-sustainable responses to conventional hepatitis B vaccination. Eleven subjects received three doses of vaccine at 56-day intervals, and five subjects received only a single vaccination. Each dose of vaccine contained 4 microg of plasmid DNA encoding the hepatitis B surface antigen (HBsAg). The vaccine was safe and well tolerated. Remarkably, the DNA vaccine elicited antibody responses in 12 of the 16 subjects after a licensed subunit vaccine failed to induce a lasting response after >/=3 vaccinations. This study provides evidence in humans for protective immunogenicity of a particle-mediated DNA vaccine in subjects who have responded suboptimally to conventional vaccination.

Adolescent↗

Cytokine production patterns and antibody response to measles vaccine.

Cytokines play an important role in the immune response to live measles virus immunization. To gain further insight into the cytokine production profile in response to measles vaccination, we studied interferon-gamma (IFN-gamma), tumor necrosis factor (TNF-alpha), soluble IL-2 receptor (sIL-2R), interleukin-2 (IL-2), interleukin-4 (IL-4), and interleukin-6 (IL-6) in both supernatants from peripheral blood mononuclear cells (PBMC) stimulated with phytohaemagglutinin (PHA), and plasma. We enrolled 57 healthy infants and children residing in an area where no measles virus circulated in their lifetimes. Overall analysis of cytokines in supernatants from PBMC showed that a predominant Th1 cytokine pattern occurs after the second dose of measles immunization. However, plasma levels of Th1 cytokines (IFN-gamma, sIL-2R and TNF-alpha) were preferentially activated by measles virus after the first dose of measles vaccination. Median IFN-gamma plasma levels were 1.73 pg/ml for infants compared to 0.63 pg/ml for older children (P = 0.003). These data suggest that after the first and the second dose of measles virus immunization, there is a predominant Th1-type directed immune response, but the Th1 cytokine pattern seems to be stronger in previously unvaccinated children. There was no correlation between cytokine production by PBMC supernatants after PHA stimulation and circulating levels of plasma cytokines. No relationship was found between any specific cytokine level and measles antibody level.

Antibodies, Viral↗

The association of class I HLA alleles and antibody levels after a single dose of measles vaccine.

Despite the success of the current measles vaccine in controlling disease in industrialized countries, the importance of vaccine failure has become increasingly apparent. Our objective was to determine if associations exist between seronegativity after measles vaccination and class I human leukocyte antigen (HLA) alleles. We undertook a cross-sectional observational study in Rochester, Minnesota, with 242 school-age children previously recruited from a communitywide seroprevalence study. We studied two groups of subjects: 72 were seronegative (EIA < or =0.8 after a single dose of measles vaccine) and 170 were seropositive (enzyme immunoassy [EIA] > or =1.0 after one dose). We used the resources of Mayo Clinic's tissue typing laboratory for serotyping class I HLA-A and HLA-B alleles via microlymphocytotoxicity assays. We found no statistically significant associations with class I HLA-A but did find associations with class I HLA-B, which includes alleles associated with seronegativity (B8, B13, and B44) and those associated with seropositivity (B7 and B51). Elucidation of the specific peptide-HLA complex interactions that lead to varying or failed immune responses may provide fertile groundwork for improved vaccines that can overcome limitations of the current live, attenuated measles vaccine.

Alleles↗

Associations between measles antibody levels and the protein structure of class II human leukocyte antigens.

In this study, we describe associations between variation in human leukocyte antigen (HLA) DP and DQ amino acid sequences and low measles antibody levels after measles immunization. We tested serum samples from 242 children for measles immunoglobulin G antibodies. We performed class II HLA typing and examined associations between DQ and DP exon 2 amino acid sequences and antibody levels. No DP amino acid variants were associated with seronegativity. However, 11 DQA and 6 DQB amino acid variants were associated with seronegativity (p<0.005). These amino acid variants were highly correlated, and the significant DQA amino acids were only found in alleles *0201, *0301, *0401, *0501, and *0601. Two of the amino acids associated with measles seronegativity were located in predicted binding pockets of the DQ molecule; one was present in the leader sequence. Among the DQB alleles, all of the amino acid variants associated with seronegativity were present only in the DQB*0201 allele. Two of the amino acids associated with seronegativity were located in predicted binding pockets of the DQ molecule; two were located in the leader sequence. Our data suggest that specific DQA and DQB amino acid variations are associated with measles seronegativity after vaccination.

Adolescent↗

Vaccine safety.

Rates of reported adverse events are remarkably low. VAERS identifies an adverse event rate approximating 11.4 reports per 100,000 vaccine doses. Approximately 15% of these reports represent SAEs, but less than 2% involve death; in most cases, reviews have shown no causal relation between the events and the vaccine. Across the spectrum of vaccines in use (including those directed against influenza and hepatitis B virus), many claims of adverse events regarding vaccines represent typical reactions to vaccinations. These reactions can be thought of as foreign-body reactions and predominate among the inactivated vaccines. In controlled studies, the adverse event rates that occur with vaccination resemble those that occur with placebo injections. Typical reactions associated with live viral and bacterial vaccines, such as MMR and varicella vaccines, may resemble attenuated forms of the disease for which the vaccine is directed. Other claims against vaccines represent chance-coincidence or misunderstood data; further studies of claims have vindicated the overall safety of the vaccines in most cases. Two documented safety concerns with vaccines, however, have demonstrated that vaccines (like other biologics and pharmacologic) can result in harm (eg, rotavirus and OPV vaccines). The denouement with these vaccines indicates the broad postmarketing data collection and evaluation that extends efforts made with prelicensure study to balance the benefits from vaccination with the risk for harm. Overall, measures including prelicensure study and postlicensure surveillance, such as VAERS, the Vaccine Safety Datalink Project, and the Clinical Immunization Safety Assessment Centers, have resulted in an exceptional safety profile for the vaccines in use.

Adult↗

Comparison of fingerstick versus venipuncture for antibody testing of measles and rubella.

The aim of this study was to determine whether the fingerstick method of obtaining blood is an acceptable alternative to venipuncture for measuring antibody levels. Blood specimens for antibody determination were obtained from healthy adult subjects by venipuncture with the serum separated from the clot by standard methodology. Fingerstick samples were also obtained by piercing the second or third finger and collected in Microtainer serum separator tubes. The serum was then separated by centrifugation, and all specimens were immediately stored at -80 degrees C until assayed. There was an excellent correlation between sera collected from fingerstick and venipuncture for both measles and rubella antibody assays. For the measles enzyme immunoassay (EIA), 85% of subjects were immune, and the correlation coefficient between the fingerstick and the venipuncture results was 0.98 using least squares linear regression. For the rubella EIA, 100% of subjects were immune, and the correlation coefficient was 0.83. Both methods showed the same number of immunopositive individuals; furthermore, there were no cases of immunity to either virus that were detected in only 1 fluid source. There was no significant difference in antibody levels from blood obtained by either method.

Adult↗

Differential HLA gene expression in measles vaccine seropositive and seronegative subjects: a pilot study.

This is the first study using GeneChip technology to elucidate genetic determinants of the measles vaccine response. A comparative gene expression study was conducted using Affymetrix's Human GeneChip U-95A in 5 human subjects immunized with a 'booster' dose of measles vaccine (Attenuax, Merck) to determine whether serologically distinct subjects exhibit differential expression of human leukocyte antigen (HLA) genes. Healthy individuals aged 15-25 y, previously immunized with 2 doses of measles-mumps-rubella-II (MMR-II) vaccine, were classified as measles vaccine immunoglobulin G-specific antibody seronegatives (n = 2) and seropositives (n = 3). Changes in expression of HLA genes in seronegatives and seropositives were studied on days 7 and 14 post-measles vaccination using Microarray Suite 5.0 (MAS 5.0). There was increased expression of the HLA class I-B (p = 0.0002), HLA class II cluster of DMA, DMB, TAP1, TAP2 (p = 0.0007) and HLA-DR (p = 0.0001) genes, and decreased expression of HLA class I MICB molecule (p = 1), HLA class I-A (p = 0.9999) and major histocompatibility complex class III HSP 70 (p = 0.9999) genes on day 7 or day 14 postvaccination in seropositives compared with seronegatives. These results suggest an association between antibody response and differential HLA gene activation and may explain one potential mechanism underlying measles vaccine non-response.

Adolescent↗

Effect of multiple freeze-thaw cycles on detection of measles, mumps, and rubella virus antibodies.

We investigated the effect of multiple freeze-thaw cycles on mumps, measles, and rubella virus serum antibody levels with whole-virus immunoglobulin G enzyme-linked immunoassays. Fresh serum samples from nine healthy adult volunteers were divided into six sets of five aliquots each. Samples were taken through a total of 10 freeze-thaw cycles and stored at 4 degrees C until assayed. Each assay measurement was done in replicates of five, and the mean value was reported. After completing 10 freeze-thaw cycles, we found no clinically or statistically significant effect on measured antibody levels and found no discernible detrimental effect on the ability to measure these antibodies by enzyme-linked immunoassays.

Adult↗

Frequency of measles virus-specific CD4+ and CD8+ T cells in subjects seronegative or highly seropositive for measles vaccine.

The protective effect of measles immunization is due to humoral and cell-mediated immune responses. Little is known about cell-mediated immunity (CMI) to measles vaccine virus, the relative contribution of CD4(+) and CD8(+) T cells to variability in such immune responses, and the immunologic longevity of the CMI after measles vaccination in humans. Our study characterizes cellular immune response in subjects seronegative or highly seropositive for measles vaccine immunoglobulin G-specific antibody, aged 15 to 25 years, previously immunized with two doses of measles-mumps-rubella II vaccine. We evaluated the ability of subjects to respond to measles vaccine virus by measuring measles virus-specific T-cell proliferation. We examined the frequencies of measles virus-specific memory Th1 and Th2 cells by an ELISPOT assay. Our results demonstrated that proliferation of T cells in seronegative subjects was significantly lower than that for highly seropositive subjects (P = 0.003). Gamma interferon (IFN-gamma) secretion predominated over interleukin 4 (IL-4) secretion in response to measles virus in both groups. The median frequency of measles virus-reactive CD8(+) T cells secreting IFN-gamma was 0.09% in seronegative subjects and 0.43% in highly seropositive subjects (P = 0.04). The median frequency of CD4(+) T cells secreting IL-4 in response to measles virus was 0.03% in seronegative subjects and 0.09% in highly seropositive subjects (P = 0.005). These data confirm the presence of measles virus-specific cellular immune responses post-measles vaccine immunization in humans. The detection of measles virus-induced IFN-gamma and IL-4 production by ELISPOT can be used to identify measles virus-specific low-frequency memory T cells in subjects immunized with measles vaccine. These differences agree in directionality with the observed antibody response phenotype.

Adolescent↗