Subclinical Reinfection Research Articles

Immune Response to the Mumps Virus in Iranian Unvaccinated Young Adults.

Although the first mumps vaccine was licensed more than 50 years ago, the vaccine was added to Iran's Expanded Program on Immunization in 2003. Therefore, the majority of Iranians born before 2003 are unvaccinated, and their immunity is the result of natural infection. In order to evaluate cellular responses against the mumps virus following natural infection, we investigated 90 Iranian unvaccinated adults aged 20-30 years. Mumps specific memory CD4+ and CD8+ proliferation and frequency of cytotoxic lymphocyte CD8+ CD107a were evaluated using flow cytometry. Our results showed that 33 subjects were seronegative, but 28 of them showed degranulation of CD8+ T lymphocytes and expression of CD 107a, as well as proliferation of CD4 and CD8 T cells, in response to mumps antigen stimulation. In all seropositive subjects, degranulation of cytotoxic T lymphocytes and proliferation of CD4+ and CD8+ T lymphocytes was detected. Proliferation of T cells and degranulation of CD8 T cells in seropositive subjects was higher than in seronegative subjects. We conclude that natural mumps infection and subclinical reinfection could induce good protection, but the severe complications associated with mumps infections suggest the need for mumps vaccination. Natural boosters because of the prevalence of the wild-type virus may help with maintenance of immunity in populations with high vaccine coverage.

Molecular studies of Varicella zoster virus

VZV is a highly cell-associated member of the Herpesviridae family and one of the eight herpesviruses to infect humans. The virus is ubiquitous in most populations worldwide, primary infection with which causes varicella, more commonly known as chickenpox. Characteristic of members of the alphaherpesvirus sub-family, VZV is neurotropic and establishes latency in sensory neurones. Reactivation from latency, usually during periods of impaired cellular immunity, causes herpes zoster (shingles). Despite being one of the most genetically stable human herpesviruses, nucleotide alterations in the virus genome have been used to classify VZV strains from different geographical regions into distinct clades. Such studies have also provided evidence that, despite pre-existing immunity to VZV, subclinical reinfection and reactivation of reinfecting strains to cause zoster is also occurring. During both primary infection and reactivation, VZV infects several PBMC and skin cell lineages. Difficulties in studying the pathogenesis of VZV because of its high cell association and narrow host range have been overcome through the development of the VZV severe combined immunodeficient mouse model carrying human tissue implants. This model has provided a valuable tool for studying the importance of individual viral proteins during both the complex intracellular replication and assembly of new virions and for understanding the underlying mechanism of attenuation of the live varicella vaccine. In addition, a rat model has been developed and successfully used to uncover which viral proteins are important for both the establishment and maintenance of latent VZV infection.

Outbreak of measles in a hospital and measures taken against hospital infection--evidence of cost and benefits

In Japan, an isolated vaccine of measles is used because MMR vaccines have been suspended due to the frequent occurrence of aseptic meningitis after their use. It is administered only once with the cover rate having been approximately 70%. An outbreak of measles was experienced in eight of our health care workers (three doctors, three nurses and two clerks of our hospital) and in seven of our medical students, accompanying local outbreaks. Their condition was severe enough to require admission to our school hospital. One of medical students developed encephalitis, but he has recovered completely. The social cost including medical cost per worker was approximately yen 500,000 (about $4,500). We measured antibodies against measles, rubella, chickenpox and mumps using the ELISA assay in 1048 health care workers less than 40 years of age and 99 medical students before their clinical practice two or three months after the outbreak. The cost including the measuring of antibodies and vaccination for these workers and students was approximately yen 2,800,000 and it will be yen 700,000 for new workers each year. The negative rates for workers were 1.2% for measles, 8.8% for rubella, 10.0% for mumps and 2.0% for chickenpox and those for the medical students were 1.0%, 22.0%, 9.0% and 5.0%, respectively. Of the workers, 9.6% who had more than the defined very high tiaer were thought to have subclinical reinfection because they were non-symptomatic. The rates were 1.2% for rubella, 0.5% for chickenpox and 0.0% for mumps for more than the defined high titers among the workers, suggesting a risk of outbreaks in the future. Therefore, the antibodies of health care workers and medical students should be measured at the hospital and the antibody-negative person should be vaccinated to prevent infection not only from their patients but also prevent other patients from becoming infected by contracted health care workers or students.

ASSOCIATION OF HEPATITIS C WITH SUBCLINICAL REACTIVATION OF HEPATITIS B VIRAL DNA DETECTED BY POLYMERASE CHAIN REACTION (PCR) IN ALLOGRAFTS OF RECIPIENTS WITH APPARENT IMMUNITY TO HEPATITIS B

355 Patients with apparent immunity to hepatitis B (anti-HBc and/or anti-HBs positivity) have been rarely reported to reactivate hepatitis B infection when immunosuppressed. We have previously reported a pretransplant prevalence of HBV DNA by PCR in HBsAg-negative, anti-HBc-positive liver recipients of 29% as detected in the recipient's native liver tissue. The post transplant course of these recipients has not been well described. AIM: To look for evidence of post transplant recurrence of hepatitis B in recipients that are HBsAg-negative, anti-HBc-positive and HBV DNA by PCR positive and also to identify any potential risk factors for recurrence. METHODS: We reviewed the data from our first 692 liver transplants (OLT), excluding HBsAg-positive recipients. 56/692 (8%) recipients were anti-HBc-positive pretransplant. 35/56 (63%) of these recipients had frozen serum samples and liver tissue from both pre and post transplant periods available for PCR analysis for HBV DNA and HCV RNA. 10/35 (29%) had detectable HBV DNA in the native recipient liver. These 10 recipients were then analyzed for recurrence of HBV DNA and stratified according to their Hepatitis C status. The mean clinical follow-up of these recipients post-OLT was 65.8 months (range 6-137). (Table)TableCONCLUSIONS: 1) Subclinical reinfection of the allograft as defined by identification of HBV DNA by PCR was seen in 4/10 (40%) of recipients that were HBsAg-negative - HBV DNA by PCR-positive pretransplant, although none of these individuals developed HBsAg-positivity. 2) Those recipients that were coinfected with hepatitis C were significantly more likely to have detectable HBV DNA than their hepatitis C negative counterparts.

Patient-to-Patient Transmission of Campylobacter pylori Infection by Fiberoptic Gastroduodenoscopy and Biopsy

Three instances of subclinical reinfection with Campylobacter pylori were observed in two successfully treated patients during follow-up of C. pylori gastritis. The reinfections occurred 1 month and 21 months (patient 1) and 32 months (patient 2) after the completion of antibacterial treatment. Sequential measurement by ELISA of serum IgG antibody levels to the microorganism showed a significant increase in two of the three instances of reinfection. Patient-to-patient transmission was proved by restriction enzyme analysis of bacterial DNA. Between patients the endoscope had been mechanically cleaned using a detergent and treated with 70% ethanol. The risk of gastroscopic cross-infection with C. pylori was estimated by retrospective analysis of the data of 281 negative examinations (107 in 47 initially negative patients and 174 in 37 cured patients). The frequency in uninfected patients of documented endoscopic transmission of C. pylori infection was 1.1% in this study, corresponding with three iatrogenic acquisitions of manifest infection for every 1000 gastroduodenoscopies in our clinic.

Immunologic evidence of reinfection with varicella-zoster virus.

Resistance to reinfection with varicella-zoster virus (VZV) was evaluated in immune adults who had household exposure to varicella. Sixty-four percent of 25 adults exposed to varicella had a fourfold or greater rise in IgG antibody to VZV or had a high initial IgG antibody titer to VZV that declined by fourfold. IgM antibody was detected in only 12% of 25 VZV-immune subjects. Seventy percent of 23 subjects exposed to varicella had IgA antibody to VZV compared with 13% of 23 subjects with antibody to VZV who had no recent exposure (P less than 0.001, chi 2 test). Enhanced cellular immunity was documented by an increase in lymphocyte transformation to VZV antigen from a mean +/- SE index of 7.8 +/- 1.30 to 15.3 +/- 2.56 (P = 0.01, paired t-test). The increase in immunity to VZV in many immune subjects exposed to VZV suggests the occurrence of subclinical reinfection.

The reactogenicity and immunogenicity of the Urabe Am 9 live mumps vaccine and persistence of vaccine induced antibodies in healthy young children

The immunogenicity and reactogenicity of the Urabe Am 9 mumps virus vaccine strain were studied after the administration of different doses of the vaccine to 197 children ranging in age from seven and a half months to nine years and without a history of mumps. There was no effect of dose on the response in serum neutralizing antibodies in the range of 10(2.9) to 10(4.7) TCID50/dose. In the 90 subjects without detectable serum neutralization antibodies before vaccination seroconversion was obtained in 94.4% after 42 days. Half of a group of 34 seropositive children who were tested also showed a fourfold or greater rise in antibodies. Persistence of vaccine-enhanced haemagluttinin-inhibition (EHI) antibodies was satisfactory as only two of 46 vaccinees followed-up for between 27 and 32 months had undetectable levels of EHI antibodies and the geometric mean titre of vaccine-induced EHI antibodies had only fallen to about one-third by 32 months after vaccination. Although there was serological evidence of a subclinical re-infection in three subjects, to date none of the vaccinees has had clinical mumps indicating that the vaccine confers protection against disease. The vaccine was well tolerated. Furthermore, the majority of the few 'reactions' reported were probably not vaccine-related. It is concluded that the Urabe Am 9 is an acceptable strain for use in live mumps vaccines.

Persistence of Antibody After Administration of Monovalent and Combined Live Attenuated Measles, Mumps, and Rubella Virus Vaccines

Hemagglutination-inhibiting antibodies were retained in comparable levels eight years after vaccination with Enders' original Edmonston and more attenuated Moraten (Attenuvax) and Schwarz line measles vaccines. Neutralizing antibody persisted without substantial decline in titer for at least 9.5 years after administration of Jeryl Lynn mumps virus vaccine (Mumpsvax). Antibodies were retained without important decline in children and adults for at least 7.5 and 7 years, respectively, after administration of HPV-77 duck-modified rubella vaccine (Meruvax). The patterns of antibody persistence 7.5 years after administration of combined measles-mumps-rubella (M-M-R) and mumps-rubella (Biavax) vaccines, 6 years after administration of measles-rubella vaccine (M-R-VAX), and 4 years after administration of measles-mumps vaccine (M-M-VAX) were the same as for the monovalent vaccines, indicating no alteration in the retention of immunity. Subclinical reinfection evidenced by increase in homologous antibody titer was observed to follow vaccination the same as occurs after natural infection.

Long-Term Follow-up for Immunity After Monovalent or Combined Live Measles, Mumps, and Rubella Virus Vaccines

Antibody in human subjects persisted without substantial decline for 8 years after mumps vaccine (Jeryl Lynn), for 6 years after measles (Attenuvax), for 5 1/2 years after rubella vaccine (HPV-77 duck), for 5 years after measles-mumps-rubella and mumps-rubella combined vaccines, for 4 years after measles and rubella, and for 2 years after measles-mumps vaccines, the longest periods tested. Protective immunity against mumps illness persisted through the eighth year. The patterns for antibody following vaccination parallel those for natural infection and indicate that immunity will be lasting. Subclinical reinfection evidenced by antibody increase was commonly seen in persons who had been vaccinated, much as follows the natural infection.

PERSISTENCE OF IMMUNITY FOLLOWING MONOVALENT AND COMBINED LIVE MEASLES, MUMPS, AND RUBELLA VIRUS VACCINES

Neutralizing antibody following Jeryl Lynn mumps virus vaccine persisted for at least six years after vaccination without substantial decline in titer, and protective immunity was solidly retained through the sixth observation year. Hemagglutination-inhibiting antibodies following vaccination with Enders' original Edmonston and more attenuated Moraten and Schwarz lines measles vaccines were retained in comparable level through the fourth year. Antibody following HPV-77 duck rubella vaccine was retained without important decline for at least 3½ years. The pattern for antibody persistence following combined measles-mumps-rubella and mumps-rubella vaccine measured at three years and for measles-rubella vaccine measured at two years was the same as for the monovalent vaccines indicating no alteration in the retention of immunity. None of the children in this study lost his antibody completely. Subclinical reinfection evidenced by antibody increase was commonly seen in vaccinated persons.

Follow-up on reubella vaccinations and experience with subclinical reinfection

Rubella antibody titers for a group to women vaccinated soon after delivery have decreased slightly after two years. None of their unvaccinated infants—even those who were breast-fed—had any serologic evidence of exposure to rubella virus. Antibody levels have been determined at annual intervals for three years on a group of institutionalized children. The geometric mean titer fell during the second year, then unexpectedly rose during the third year suggesting subclinical reinfections. The incidence of subclinical reinfection was very low among RA 27/3 vaccinees and naturally immune children, but it was 26 per cent among recipients of the Cendehill vaccine. Results suggest that with presently licensed rubella vaccines it is not possible to produce a “herd immunity,” at least, not in an institutional population.

A Study of Rubella Immunity and Resistance to Infection

During a rubella outbreak, the effect of exposure on 33 susceptible persons, 22 vaccinees, and 66 others with immunity from earlier rubella was studied. Groups were examined daily and specimens were collected for virologic testing. Infection occurred in 22 of the susceptible persons; all tested were viremic, excreted copious amounts of virus, and had clinical rubella. None of the previously vaccinated or naturally immune individuals developed rubella. Antibody boosts indicative of subclinical reinfection occurred in five vaccinees and one naturally immune child; these six were not demonstrably viremic, and only two vaccinees excreted virus. Antibody level appeared to influence resistance to reinfection. However, any detectable antibody protected against disease, prevented viremia, and blocked or modified pharyngeal virus replication. It was concluded that rubella exposure of vaccinees with antibodies was unlikely to constitute a significant clinical or epidemiologic risk.

Research on dengue during World War II.

Summary Research on dengue in the U. S. during World War II provided the following new information of special interest to military preventive medicine: 1. Proof of the existence of multiple immunological types of dengue. 2. The long persistence of immunity to homologous types of virus under conditions precluding reenforcement of immunity by subclinical reinfection. 3. The modifications of the clinical manifestations of the disease which result from reinfection with a heterologous type of virus at various periods after the primary attack. 4. The demonstration that in areas (e.g., New Guinea) where more than one imunological type of virus is present, fevers of unknown origin, clinically not recognizable as dengue, are actually caused by the dengue viruses. 5. The demonstration that type-specific immunity to dengue is associated with neutralizing antibodies for the virus, which can be used for diagnostic and epidemiologic survey purposes. 6. The propagation of dengue virus in mice with the resulting appearance of a mutant or variant strain which could be used for active immunization. In addition to the discoveries listed above, a great deal more was learned about the basic properties of the dengue viruses. Thus was dengue research brought from the field into the laboratory and further progress has been made possible by work on experimental animals instead of on human volunteers.