Harry L. Keyserling

2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

Safety and Immunogenicity of Heptavalent Pneumococcal Vaccine Conjugated to CRM197 in United States Infants

Objective. To determine the safety and immunogenicity of heptavalent pneumococcal saccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) individually conjugated to CRM197 (PNCRM7), administered at 2, 4, 6, and 12 to 15 months of age. Design. Two hundred twelve healthy 2-month-old infants were equally randomized to receive four consecutive doses of PNCRM7 or an investigational meningococcal group C conjugate vaccine, which served as a control. Concomitantly administered routine vaccines were oral polio vaccine and combined diphtheria toxoid, tetanus toxoid, and whole cell pertussis vaccine/Haemophilus influenzae type b vaccine consisting of capsular oligosaccharides conjugated to CRM197 (DTP/HbOC) at 2, 4, and 6 months, and either measles-mumps-rubella vaccine or HbOC at 12 to 15 months. Active safety surveillance was conducted for 3 days after each dose. Antibody concentrations to each of the 7 pneumococcal serotypes were measured by enzyme-linked immunosorbent assay prevaccination, after doses two and three, prebooster, and postbooster. Results. Significantly fewer children experienced local reactions at the PNCRM7 injection site than at the DTP/HbOC site. There was no increase in the incidence or severity of local reactions at the PNCRM7 site with increasing doses of vaccine. Mild to moderate postvaccination fever was common in both the PNCRM7 and control vaccine groups, however DTP/HbOC was administered concurrently. All 7 vaccine serotypes were immunogenic. The kinetics of the immune responses were serotype-specific. After three doses of PNCRM7, between 92% to 100% of children had ≥0.15 μg/mL of antibody, and 51% to 90% achieved a level of ≥1 μg/mL against specific serotypes. A booster dose of PNCRM7 resulted in a brisk anamnestic response to all 7 vaccine serotypes, demonstrating effective stimulation of T-cell memory by the primary series of vaccinations. Conclusion. Primary immunization followed by a booster dose of PNCRM7 seemed to be acceptably safe and resulted in significant rises in antibody to all 7 serotypes. Implications. Studies to assess vaccine efficacy of PNCRM7 for prevention of systemic disease, nasopharyngeal colonization, and acute otitis media are in progress. If PNCRM7 proves to be protective, there is the potential to prevent up to 85% of invasive pneumococcal disease occurring in US children.

Executive Summary: 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response

The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8+ T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8+ T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8+ T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8+ T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8+ T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-γ, TNF-α, IL-2, and MIP-1β. 4) The YF-17D-specific memory CD8+ T cells had a phenotype (CCR7−CD45RA+) that is typically associated with terminally differentiated cells with limited proliferative capacity (TEMRA). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8+ T cells generated after acute viral infections.

Clostridium difficile Infection in Infants and Children

Infections caused by Clostridium difficile in hospitalized children are increasing. The recent publication of clinical practice guidelines for C difficile infection in adults did not address issues that are specific to children. The purpose of this policy statement is to provide the pediatrician with updated information and recommendations about C difficile infections affecting pediatric patients.

Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: Results of a phase I/II trial

BACKGROUND Neonatal herpes simplex virus (HSV) infections limited to the skin, eyes and mouth (SEM) can result in neurologic impairment. A direct correlation exists between the development of neurologic deficits and the frequency of cutaneous HSV recurrences. Thus, the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted a Phase I/II trial of oral acyclovir therapy for the suppression of cutaneous recurrences after SEM disease in 26 neonates. METHODS Infants < or = 1 month of age with virologically confirmed HSV-2 SEM disease were eligible for enrollment. Suppressive oral acyclovir therapy (300 mg/m2/dose given either twice daily or three times per day) was administered for 6 months. RESULTS Twelve (46%) of the 26 infants developed neutropenia (< 1000 cells/mm3) while receiving acyclovir. Thirteen (81%) of the 16 infants who received drug 3 times per day experienced no recurrences of skin lesions while receiving therapy. In comparison, a previous Collaborative Antiviral Study Group study found that only 54% of infants have no cutaneous recurrences in the 6 months after resolution of neonatal HSV disease if oral acyclovir suppressive therapy is not initiated. In one infant, HSV DNA was detected in the cerebrospinal fluid during a cutaneous recurrence, and an acyclovir-resistant HSV mutant was isolated from another patient during the course of the study. CONCLUSIONS Administration of oral acyclovir can prevent cutaneous recurrences of HSV after neonatal SEM disease. The effect of such therapy on neurologic outcome must be assessed in a larger, Phase III study. As such, additional investigation is necessary before routine use of suppressive therapy in this population can be recommended.

Recommendations for Prevention and Control of Influenza in Children, 2012–2013

The purpose of this statement is to update recommendations for routine use of trivalent seasonal influenza vaccine and antiviral medications for the prevention and treatment of influenza in children. The key points for the upcoming 2012–2013 season are: (1) this year’s trivalent influenza vaccine contains A/California/7/2009 (H1N1)–like antigen (derived from influenza A [H1N1] pdm09 [pH1N1] virus); A/Victoria/361/2011 (H3N2)–like antigen; and B/Wisconsin/1/2010–like antigen (the influenza A [H3N2] and B antigens differ from those contained in the 2010–2011 and 2011–2012 seasonal vaccines); (2) annual universal influenza immunization is indicated; and (3) an updated dosing algorithm for administration of influenza vaccine to children 6 months through 8 years of age has been created. Pediatricians, nurses, and all health care personnel should promote influenza vaccine use and infection control measures. In addition, pediatricians should promptly identify influenza infections to enable rapid treatment, when indicated, to reduce morbidity and mortality.

Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination

Rates and severity of pneumococcal infections in children with sickle cell disease were examined before licensure of pneumococcal-conjugated vaccine (PVC). Rates of peak invasive infection rates in 1-year-old children with hemoglobin SS and mortality in those 0 to 10 years of age were 36.5 to 63.4 and 1.4 to 2.8 per 1000 person-years, respectively (>10 and 100 times as frequent as in the general population). Overall, 71% of serotyped isolates (n=80) were PVC serotypes and 71% of nonvaccine serotype strains were penicillin-sensitive. Clinical presentation in children with hemoglobin SS (n=71; more with hypotension) and hemoglobin SC (n=18; more with acute chest syndrome, otitis media) differed. Penicillin nonsusceptibility (38% of isolates) varied between geographic study sites. Penicillin prophylaxis appeared less effective against intermediate and resistant strains. Of all infected children, meningitis developed in 20% and 15% died (hemoglobin SS, n=15 and 11; hemoglobin SC, n=1 each). Factors associated with death included age >4 years (58%), serotype 19F, and not being followed by a hematologist (42% each). The pneumococcal-polysaccharide vaccine was 80.4% effective within 3 years after vaccination (95% CI, 39.7, 93.6). Children with sickle cell disease of all ages may benefit from PVC boosted with polysaccharide vaccination.

A randomized comparison of three bivalent Streptococcus pneumoniae glycoprotein conjugate vaccines in young children: effect of polysaccharide size and linkage characteristics.

Because most childhood invasive pneumococcal disease occurs before the age of 2 years, the development of a pneumococcal vaccine that is immunogenic in infants is a priority. We assessed the safety and serum antibody responses to two dose levels of three bivalent pneumococcal capsular polysaccharide (CPS)-protein conjugate vaccines incorporating the poorly immunogenic serotypes 6A and 23F. The conjugate vaccines differed in CPS size and chemical linkage, but all used a nontoxic cross-reactive mutant diphtheria toxin (CRM197) as the protein carrier. 118 young children 18 to 30 months of age received a single immunization with one of the three glycoconjugates or with licensed pneumococcal vaccine. Sera were obtained before and 1 month after immunization and analyzed by enzyme-linked immunosorbent assay for serotype-specific antibody titers. The 23F CPS was more immunogenic than the 6A CPS in all vaccine formats. The most immunogenic 23F conjugate vaccine consisted of native CPS directly linked to the carrier protein; smaller CPS or the use of a six-carbon linker did not appear to enhance immunogenicity in these young children. Conjugation of two pneumococcal CPSs is associated with an increase in immunogenicity, and the characteristics of the CPS and of the CPS-protein linkage appear to influence the antibody response.

Immunologic priming of young children by pneumococcal glycoprotein conjugate, but not polysaccharide, vaccines

BACKGROUND Streptococcus pneumoniae is the most common cause of invasive bacterial disease and otitis media in infants and young children. Licensed pneumococcal polysaccharide vaccines are not reliably immunogenic in children younger than 2 years of age; therefore pneumococcal glycoprotein conjugate vaccines are currently being evaluated for safety, immunogenicity and efficacy in various age groups. METHODS During a 12-month period we determined the kinetics of pneumococcal IgG antibody in 60 children who received primary immunization with one dose of bivalent (serotypes 6A and 23F) pneumococcal polysaccharide-CRM197 vaccines at 18 to 30 months of age. To assess immunologic priming a subgroup of 20 subjects received secondary immunization with pneumococcal polysaccharide vaccine, including serotypes 6B and 23F, at 11 to 20 months after primary immunization. Pneumococcal-specific IgG subclass distributions were also evaluated in the subgroup. RESULTS In the 12 months after primary immunization with glycoprotein conjugate vaccine, geometric mean pneumococcal IgG antibody concentrations to 6B and 23F serotypes remained stable. Pneumococcal polysaccharide vaccine induced a greater anamnestic response in children primed with glycoprotein conjugate vaccines (13- to 40-fold increases to geometric mean concentrations of 6 to 30 micrograms/ml for type 23F), than in those primed with polysaccharide (2- to 4-fold increases). A greater IgG response to pneumococcal serotype 23F than to 6B was observed with both primary and secondary immunization. The serotype-specific pneumococcal IgG antibody response was virtually restricted to the IgG1 subclass after primary immunization, but secondary immunization elicited antibodies of IgG1 and IgG2 subclasses. CONCLUSIONS These glycoprotein conjugate vaccines appear to prime for anamnestic IgG antibody responses to subsequent immunization with polysaccharide vaccine, suggesting that the polysaccharide-CRM197 vaccine effectively induces a predominantly T cell-dependent immune response. The greater IgG response to 23F than to 6B indicates that pneumococcal serotype is a major determinant of immunogenicity of pneumococcal glycoprotein conjugate vaccines.