All great enduring bodies and societies began by small gatherings of persons to share their learned experiences and thoughts that all may be recorded for posterity. And so it was with this august body, the Pediatric Infectious Diseases Society (PIDS). The idea for the PIDS was born from Stanley A. Plotkin’s perspicacious thought (Figure 1) that clearly infectious diseases was an important specialty in pediatrics, and although adult infectious diseases had been established as a legitimate subspecialty, pediatric infectious diseases (PID) had not. “Of course, there were many practioners of PID, most of whom I knew, but they almost all complained about their lack of recognition by department chairs.” Moreover, no board or certification existed. Stanley thought that if the people who were doing PID could be brought together, the “invisible college” that already existed could become discernible, and when visible might start organizing itself. The idea was discussed with a number of Stanley’s friends, notably Phil Brunell, David Karzon, Vickie Schauf, and Scott Giebink, and all were enthusiastic. Although yet to be officially baptized or recognized, the seed for a future annual assemblage of PID specialists was planted, but unfunded. Hence, Stanley wrote to 12 pharmaceutical companies requesting support for his novel venture. He noted that he had “canvassed about 70 people in the field, and enthusiasm has been practically unanimous. I expect that practically everyone in the field attending the meeting will also attend the dinner. Furthermore, since the dinner will be rather expensive if not subsidized, I am asking for a contribution of $750 from each firm. Frankly, anything less than $500 will not be helpful.” Of the 12 companies, most sent their polite regrets. Four contributed between $250 and $750 to a grand total of $2500. With this trove treasured in the bank, Stanley sent letters to all heads of PID fellowship programs announcing that he was convening a meeting of PID specialists during the 1978 American Pediatric Society-Society for Pediatric Research (APS-SPR) meeting. Anyone practicing PID full-time in an academic center was invited. The first official meeting of the Pediatric Infectious Diseases Club was held on April 27, 1978 at the New York Hilton (New York City, NY) with cocktails, dinner, and a program on measles vaccination by James Cherry, Samuel Katz, and Saul Krugman. Ninety-seven people attended and, of note, the cost for this 4-course dinner at the Hilton was $7.50 per person. Following this program, a very lively discussion concerning the formation of a recognized PID group ensued. Many insisted that no formal organization was necessary; PID was not and should not be a formal specialty, and this would lead to an additional abhorrent board examination. But many argued that making PID a specialty would be necessary for professional recognition, and general pediatricians could Special Article

Generating broadly neutralizing antibodies with candidate vaccines has remained an elusive goal. Consequently, vaccine candidates developed have aimed at eliciting cell-mediated immune effector activities (CMI) that could delay disease progression, and maybe also limit secondary transmission, by controlling virus replication. There is considerable discussion about what types of endpoints would constitute definable standardized clinical benefit to the individual that would result in licensure of these candidate vaccines. Identifying biomarkers that can be used as surrogates for clinical endpoints in randomized clinical trials would be useful, because it would shorten studies and reduce costs. Biological markers associated with disease progression and secondary transmission and that may be used as prognosis markers and surrogate endpoints in HIV vaccine trials have emerged from analyses of data from studies on natural history of HIV infection. Extensive literature is cited to support the use of plasma viral load as a primary endpoint for supporting licensure decisions. Overall, a significant result on viral load in a vaccine trial should be considered as a significant breakthrough for vaccines and be aggressively pursued with the caveat that such a result should rapidly be followed by well-defined studies to verify durable virological and immunological vaccine benefit, as well as ultimate clinical benefit. The review also provides perspectives on magnitude of viral load reduction, durability of viral load reduction for reduced progression of HIV disease.

The goal of eliminating indigenous rubella and congenital rubella syndrome (CRS) in the United States in the near future is now within reach, because rubella incidence has been sustained at record-low levels since the mid-1990s. Effective prevention strategies to eliminate CRS and rubella require improvement in the surveillance of CRS and congenital rubella infection (CRI). The purpose of the workshop was to review rubella and CRS epidemiology, as well as current clinical, diagnostic, and laboratory practices, to determine whether new strategies are needed to achieve and document CRS elimination. Workshop participants agreed that surveillance for CRS must be strengthened, particularly through augmented laboratory capabilities, and the case definition for CRS must be revised to reflect the current scientific information available. Further studies of methods are needed to identify high-risk populations and geographic areas for rubella and CRS and to enhance identification of infants with CRS.

A live recombinant canarypox vector expressing HIV-1 gp120 MN tm/gag/protease LAI (ALVAC-HIV, vCP205) alone or boosted by a p24E-V3 MN synthetic peptide (CLTB-36) was tested in healthy volunteers at low risk for HIV infection for their safety and immunogenicity, Both antigens were well tolerated. ALVAC-HIV (vCP205) induced low levels of neutralizing antibodies against HIV-1 MN in 33% of the volunteers. None of them had detectable neutralizing antibodies against a nonsyncytium-inducing HIV-1 clade B primary isolate (Bx08). After the fourth injection of vCP205, CTL activity was detected in 33% of the volunteers and was directed against Env, Gag, and Pol, This activity was mediated by both CD4(+) and CD8(+) lymphocytes, On the other hand, the CLTB-36 peptide was poorly immunogenic and induced no neutralizing antibodies or CTLs. Although the ALVAC-HIV (vCP205) and CLTB-36 prime-boost regimen was not optimal, further studies with ALVAC-HIV (vCP205) are warranted because of its clear induction of a cellular immune response and utility as a priming agent for other subunit antigens such as envelope glycoproteins, pseudoparticles, or new peptides.

To assess the cost of varicella in young children in France, a prospective study was done in day care centers. Children (1263), who were 3 months to 3 years old and attending day care, were followed over a varicella season. For every child who developed varicella (n = 200), detailed information was obtained by use of parental questionnaires. Questions concerned medical care, days missed from work for parents, and the need for extra baby-sitting. On average, each sick child had one consultation with a physician and received three medications. In half of the families (52%), at least 1 parent had to miss work an average of 4.5 days to care for a sick child. Total costs to society were estimated to be US$352 per family, with medical costs accounting for 22% of the cost. The average eventual cost to parents was $89 per family, including $80 of non-medical costs. This study emphasizes the important socioeconomic impact of varicella in the day care setting in France.

Avian poxvirus recombinants undergo abortive replication in nonavian cells, yet can achieve expression of extrinsic gene products. Canarypox-vectored vaccines have been innocuous and immunogenic in several mammalian species. ALVAC-RG, a canarypox recombinant expressing the rabies glycoprotein gene, was inoculated intramuscularly into adult volunteers on days 0, 28, and 180. Sequential cohorts received 10(3.5), 10(4.5), and 10(5.5) 50% tissue culture infective doses (TCID50); additional volunteers received the standard human diploid cell rabies vaccine (HDCV) on the same schedule. Reactogenicity of ALVAC-RG was minimal. The lowest dose of ALVAC-RG induced little antibody to rabies virus by ELISA or rapid fluorescent focus inhibition test (RFFIT), but 10(4.5) and 10(5.5) TCID50 doses elicited significant responses in both assays. All recipients of 10(4.5) and 10(5.5) TCID50 of ALVAC-RG attained RFFIT values above the presumed protective level. Canarypox-specific immune responses did not inhibit boosting of rabies-specific antibodies by the day 180 dose of ALVAC-RG. T cell proliferation in response to inactivated rabies virus in vitro was similar in HDCV and ALVAC-RG recipients after the first and second doses, although HDCV yielded superior results after the third dose. ALVAC-RG was safe in humans, induced functional antibody to rabies glycoprotein, elicited cellular responses to rabies virus, and could be used successfully for booster dosing at a 6 month interval.

Poxviruses have many useful features as vectors for genes that carry immunising antigens from other viruses, such as ease of production and induction of cellular and humoral immunity, but there is concern about the safety of vaccinia virus. We turned to an avian poxvirus (canarypox); this virus undergoes abortive replication in mammalian cells that enables presentation of early gene products to the immune system. Canarypox virus was used as a vector for the rabies glycoprotein G gene.The safety and efficacy of the recombinant (ALVAC-RG; vCP65) were tested in several animal species, then it was subjected to a phase 1 clinical trial. Twenty-five volunteers were randomly assigned to subcutaneous injections of the recombinant (three groups [A, B, and C] received two doses each of 10(3.5), 10(4.5), and 10(5.5) tissue-culture infectious doses50, respectively) or of human diploid cell culture vaccine (HDC; 6.52 international potency units per dose). 28 days after the second dose, all nine ALVAC-RG group-C subjects and two of three group-B subjects had rabies neutralising antibody concentrations of at least 0.5 IU/ml, the level associated with protection in animals. Although the geometric mean titre of these antibodies at that time was lower in group C than in the ten HDC recipients (4.4 [range 0.9-12.5] vs 11.5 [4.7-25.3] IU/ml), a single booster dose at 6 months induced a recall response in volunteers primed with either vaccine. Side-effects associated with ALVAC-RG were mild and of short duration and occurred at similar frequency to those of HDC vaccine.This study has shown the potential of non-replicating poxviruses as vectors for vaccination in human beings. Trials of canarypox-virus recombinants at higher doses and by other routes of administration are needed.

A polyribosylribitol phosphate (polysaccharide)-tetanus protein conjugate vaccine (PRP-T) against Haemophilus influenzae type b (Hib) was evaluated for safety and efficacy after vaccination of more than 100,000 infants. No major side effects were attributed to the vaccine. Immunogenicity studies showed an antibody response in 70% to 100% of infants after two doses, and in 98% to 100% of infants after three doses, within the first 6 months of life. Antibodies persisted in 90% of recipients, in whom significant anamnestic responses developed after a booster dose at 18 months of age. In comparison with other available Hib vaccines, PRP-T induces equal or higher mean titers after three doses. Although licensure of other vaccines interrupted controlled efficacy trials, up to that point five cases of Hib disease in those trials had occurred in placebo recipients, and no Hib disease has been reported in the more than 100,000 vaccinated infants who have received more than one dose of PRP-T. Thus PRP-T combined immunogenicity early in life with induction of immunologic memory.

The human cytomegalovirus (HCMV), Towne strain, glycoprotein B (gB) gene was cloned into a vaccinia vector (Copenhagen strain) under the control of the H6 early and late vaccinia promoters (Vac-gB recombinant). The gB protein was expressed in a high percentage of the Vac-gB-infected cells throughout the virus replication cycle. Cytosine-arabinoside (ara-C) did not influence the expression of the gB protein early after infection (5 h), but did inhibit it later in viral replication (7-29 h). The Vac-gB recombinant induced HCMV neutralizing antibodies in guinea-pigs. Cells infected with the Vac-gB recombinant absorbed 50-88% of neutralizing activity of human sera obtained from volunteers previously inoculated with the Towne or Toledo strains and from naturally seropositive individuals.

Cell surface expression of stage specific embryonic antigen 1 (SSEA-1), or Lex (III3 FucnLC4), was induced in differentiated human teratocarcinoma cells and in human diploid fibroblasts 3-6 d after infection with human cytomegalovirus (HCMV). In parallel, fucosylated lactoseries glycolipids bearing the SSEA-1/Lex epitope were readily detected in the infected cells but not in the uninfected cells. HCMV infection also results in altered expression of several glycosyltransferases. SSEA-1/Lex induction is probably a consequence of both increased expression of beta 1----3N-acetylglucosaminyltransferase, which catalyzes the rate-limiting step in lactoseries core chain synthesis, and subtle alterations in the relative competition for common precursor structures at key points in the biosynthetic pathway. Since SSEA-1 has been suggested to play a role in some morphogenetic cell-cell interactions during embryonic development, the induction of this antigen at inappropriate times might provide one mechanism whereby intrauterine infection with HCMV can damage the developing fetal nervous system.

A 2-yr. study was begun to evaluate the use of FTW-RBC in preventing TA-CMVI and the severity of TA-CMVI in neonates. Neonates weighing 2 kg or less were randomized to receive either liquid-stored RBC (RBC) (Gr.I) or FTW-RBC (Gr.II). CMV antibody was measured in sera from mothers and neonates (pre- and 2 mo. post-Tx). Viral cultures were done every 2 wk. 296/853 (35%) donors were seropositive (CMV Ab+). Of 71 infants analysed, 41/45 (91%) in Gr.I and 20/26 (77%) in Gr.II received CMV Ab+ blood at least once. No infant in either group receiving seronegative (CMV Ab-) blood developed TA-CMVI. The incidence of TA-CMVI in infants receiving CMV Ab+ RBC in Gr.I was 24.4% (10/41); 2/10 were born to CMV Ab+ mothers. In Gr.II, one infant seroconverted prior to Tx of CMV Ab+ FTW-RBC, suggesting nursery-acquired CMVI (NA-CMVI). In Gr.I, the mean number of Tx (19.2 vs 11.2, p<0.02) and donor exposures (12.8 vs 7.1, p<0.01) were significantly higher in infants with TA-CMVI than in CMV Ab- infants. In Gr.II, no infant, including the one with NA-CMVI, acquired TA-CMVI despite receiving the same mean number of CMV Ab+ blood Tx as did Gr.I infants. This suggests cryopreservation prevents TA-CMVI. As to severity, 1/10 infants with TA-CMVI developed hepatitis and recovered uneventfully; none died. Our preliminary data support the concept that the use of FTW-RBC or CMV Ab- RBC prevents TA-CMVI, although TA-CMVI appeared to be mild in the neonates studied.