Strategies for prevention of RSV nosocomial infection.

OBJECTIVE: To review the literature on respiratory syncytial virus (RSV) as a cause of nosocomial infections (NI) on neonatal intensive care units (NICUs) and pediatric wards, and the effectiveness of various containment strategies. STUDY DESIGN: We conducted a literature review to define characteristics of RSV NI, and to evaluate the relative effectiveness of various infection containment programs, including the use of palivizumab on the reported incidence of RSV NI on NICUs and pediatric wards. RESULT: Highly variable rates of RSV NI have not significantly changed since RSV was first identified. The evaluation of the effectiveness of containment strategies has relied on before/after study designs. Focus on rapid patient diagnosis, compliance of acceptable handwashing techniques and cohorting of patients and staff appears to form the backbone of most prevention and containment programs. When these or other measures have failed, the administration of palivizumab has been useful in halting the spread of RSV NI in children. CONCLUSION: RSV NI continues to be prevalent in the NICU despite adoption of infection control programs. Preventive measures should be employed to lower the risk of RSV NI and, if identified, appropriate containment strategies should be rapidly implemented.

Controlling invasive pneumococcal disease: is vaccination of at-risk groups sufficient?

Risk factors for invasive pneumococcal disease (IPD) include young and old age, comorbidities (such as splenic dysfunction, immunodeficiencies, chronic renal disease, chronic heart or lung disease or cerebral spinal fluid leak), crowded environments or poor socioeconomic conditions. Universal use of the 7-valent pneumococcal conjugate (7vPncCRM) vaccine for infants and young children has led to significant decreases in IPD in the vaccinated population (direct protection), and there has also been a decrease in the incidence of IPD among the nonvaccinated population (indirect immunity; herd protection). While 7vPncCRM vaccine is administered universally to children in USA, many countries of the European Union have chosen to target children with comorbidities. This review aims to highlight individual risk factors for IPD, describe studies that evaluated pneumococcal conjugate vaccines in at-risk groups and estimate the proportion of at-risk children who may have been vaccinated in the European Union since the 7vPncCRM vaccine was introduced, using UK as an example. Although immunisation targeting only children with comorbidities may achieve satisfactory results for a few, many otherwise healthy children at risk simply because of their age will be neglected, and herd protection might not be established.

Vaccines for neonatal viral infections: towards a live respiratory syncytial virus vaccine:a study in risk.

There is risk attached to the development of respiratory syncytial virus vaccines, live attenuated or otherwise, but without the acceptance of this risk by manufacturers, health providers and the public, the conclusion of successful Phase III trials may lie in the distant future.

Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine.

OBJECTIVE: To evaluate the impact of the introduction and routine use of seven valent pneumococcal conjugate vaccine on the epidemiology of invasive pneumococcal disease within the Northern California Kaiser Permanente (KP) population. METHODS: Surveillance for invasive pneumococcal disease has been in place within KP since 1995. Isolates from normally sterile sites in children are routinely sent for serotyping. Cases of invasive disease are identified through review of automated microbiology records within KP. Incidence rates of invasive disease were compared for the period before and after routine use of pneumococcal conjugate vaccine in children. RESULTS: The incidence of invasive pneumococcal disease caused by vaccine serotypes before the licensure and routine use of pneumococcal conjugate vaccine ranged between 51.52 and 98.15 cases per 100 000 person years in children <1 year of age and fell to 9.35 after introduction of vaccine. The incidence in children <2 years of age was 81.67 to 113.80 before introduction and 38.22 cases per 100 000 person years after introduction of the vaccine into the general population. These reductions in disease rates exceeded the average vaccine coverage substantially in each age group. No increase in disease incidence was observed for possibly cross-reacting serotypes or nonvaccine serotypes. CONCLUSION: The introduction and routine use of pneumococcal conjugate vaccine in our population have been associated with a substantial reduction in invasive disease incidence in children <5 years of age.

Safety and immunogenicity of four doses of Neisseria meningitidis group C vaccine conjugated to CRM197 in United States infants.

BACKGROUND: Following widespread use of conjugate pneumococcal vaccine, Neisseria meningitidis likely will become the leading cause of bacterial sepsis and meningitis in US children. This report describes the safety and immunogenicity in US children of four consecutive doses of a meningococcal group C vaccine conjugated to CRM197 via reductive amination (MnCC). METHODS: One hundred six healthy 2-month-old infants received MnCC at 2, 4 and 6 months of age in a randomized, controlled double blind study; children in the other treatment arm were given a 7-valent conjugate pneumococcal vaccine. Parents reenrolled 64 of these children at 12 to 15 months to receive a fourth dose of MnCC. Routine childhood vaccines, including DTP, were coadministered. Temperatures and symptoms were recorded for 3 days after each immunization. Serum enzyme-linked immunosorbent assay IgG and bactericidal antibodies were measured prevaccination and before and 1 month after Doses 3 and 4. RESULTS: Moderate to severe local reactions, defined as erythema or induration > or =2.4 cm or pain that interfered with limb movement was reported after 0 to 3.2% of MnCC injections, depending on the reaction and dose. Fever occurred in 23 to 37% of children, but the contribution of MnCC to the febrile reactions is unknown. Geometric mean concentrations of IgG antibody to group C meningococcal polysaccharide were 3.72 microg/ml after Dose 3 and 8.03 microg/ml after the booster. Geometric mean functional serum bactericidal antibody titers after Doses 3 and 4 were 1:463 and 1:2341, respectively. One hundred percent of children had a serum bactericidal antibody titer of > or =1:64 after three doses and > or = 1:128 after the booster. CONCLUSIONS: The MnCC vaccine had an acceptable safety profile and generated high titers of bactericidal antibody in immunized US infants and toddlers. It appears to be an attractive candidate vaccine for the prevention of serogroup C meningococcal disease in young children.

Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group.

OBJECTIVE: To determine the efficacy, safety and immunogenicity of the heptavalent CRM197 pneumococcal conjugate vaccine against invasive disease caused by vaccine serotypes and to determine the effectiveness of this vaccine against clinical episodes of otitis media. METHODS: The Wyeth Lederle Heptavalent CRM197 (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a double blind trial; 37,868 children were randomly assigned 1:1 to receive either the pneumococcal conjugate vaccine or meningococcus type C CRM197 conjugate. The primary study outcome was invasive disease caused by vaccine serotype. Other outcomes included overall impact on invasive disease regardless of serotype, effectiveness against clinical otitis media visits and episodes, impact against frequent and severe otitis media and ventilatory tube placement. In addition the serotype-specific efficacy against otitis media was estimated in an analysis of spontaneously draining ears. RESULTS: In the interim analysis in August, 1998, 17 of the 17 cases of invasive disease caused by vaccine serotype in fully vaccinated children and 5 of 5 of partially vaccinated cases occurred in the control group for a vaccine efficacy of 100%. Blinded case ascertainment was continued until April, 1999. As of that time 40 fully vaccinated cases of invasive disease caused by vaccine serotype had been identified, all but 1 in controls for an efficacy of 97.4% (95% confidence interval, 82.7 to 99.9%), and 52 cases, all but 3 in controls in the intent-to-treat analysis for an efficacy of 93.9% (95% confidence interval, 79.6 to 98.5%). There was no evidence of any increase of disease caused by nonvaccine serotypes. Efficacy for otitis media against visits, episodes, frequent otitis and ventilatory tube placement was 8.9, 7.0, 9.3 and 20.1% with P < 0.04 for all. In the analysis of spontaneously draining ears, serotype-specific effectiveness was 66.7%. CONCLUSION: This heptavalent pneumococcal conjugate appears to be highly effective in preventing invasive disease in young children and to have a significant impact on otitis media.

Vaccination of seropositive subjects with CHIRON CMV gB subunit vaccine combined with MF59 adjuvant for production of CMV immune globulin.

The safety and immunogenicity of four different regimens of CHIRON cytomegalovirus (CMV) gB subunit vaccine combined with MF59 adjuvant and administered to seropositive plasma donors were evaluated to ascertain whether vaccination of seropositive subjects would significantly increase antibody titer to gB glycoprotein. This was done to select the best vaccination regimen for generating high-titered plasma for manufacture of CMV immune globulin. No serious adverse events were attributed to this vaccine, and the vaccine was well tolerated. Only the first dose of vaccine in each regimen stimulated a four-fold or greater antibody response to gB glycoprotein and each regimen induced similar antibody titers. However, initial vaccination followed by a 1 week rest from plasmapheresis and two booster vaccinations at 8 and 24 weeks, each followed with another 1 week rest from plasmapheresis, maintained the highest geometric mean gB ELISA titer of the four regimens over the 34-week post-vaccination period. CMVIG manufactured from a pool of high titered plasma units from two of four subject groups had gB ELISA and neutralizing antibody titers nine and six times higher, respectively, compared to Cytogam, indicating that vaccination of seropositive subjects with CHIRON gB vaccine combined with MF59 adjuvant prior to harvesting plasma can enhance functional antibody in a CMVIG product.

Sequential annual administration of purified fusion protein vaccine against respiratory syncytial virus in children with cystic fibrosis.

BACKGROUND: We recently showed the clinical benefit of the PFP-2 vaccine for respiratory syncytial virus (RSV) for children with cystic fibrosis (CF). OBJECTIVE: To determine the safety and immunogenicity of yearly sequential administration of the PFP-2 vaccine in CF children. STUDY DESIGN: Twenty-nine of the 34 CF children who participated in the previous study were enrolled in this open label vaccine study. All of the CF children ages 2.6 to 8.9 years received the PFP-2 vaccine, the PFP/PFP group received the PFP-2 vaccine in 1993 and 1994 and the saline/PFP group received the vaccine for the first time in 1994. At entry demographic data and measurements of lung function and nutrition were collected. Microneutralization test, enzyme-linked immunosorbent assay to F protein and Western blot assay were performed on plasma drawn before and 4 weeks after vaccination and at the end of the RSV season. During the study weekly telephone calls were made and acute respiratory illnesses were evaluated. RESULTS: Baseline measurements were similar between groups. Systemic and local vaccine reactions were mild and similar for both groups. A 4-fold or greater neutralizing antibody rise to RSV occurred in 4 of 14 (28.6%) and 9 of 14 (64.3%) in PFP/PFP and saline/PFP groups (P = 0.13), respectively. Four children in the PFP/PFP group and 7 in the saline/PFP group were infected with RSV. A reduction in lower respiratory illnesses (1.0 vs. 2.0), antibiotic courses (2.5 vs. 5.6) and days of illnesses (37.3 vs. 93.1) was observed in the PFP/PFP vaccinees infected with RSV compared with the saline/PFP group (t test; P < or = 0.05). One death occurred in the PFP/PFP group; the cause of death was consistent with septic shock and unrelated to vaccination or RSV infection. CONCLUSION: Sequential annual PFP-2 vaccination was safe and not associated with exaggerated respiratory disease.

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 microg/mL of antibody, and 51% to 90% achieved a level of >/=1 microg/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.

Safety profile of WinRho anti-D.

WinRho anti-D is manufactured with multiple processes to minimize the risk of transmitting blood-borne diseases such as viruses. These safety features include donor selection, plasma testing, solvent-detergent viral inactivation, and nanofiltration. To date, there has not been any case of viral transmission in association with use of WinRho anti-D. Adverse drug reactions are infrequent and generally mild; the most common are headache, fever, and chills. Some degree of hemolysis is inevitable due to the mechanism of action of WinRho anti-D, but this is predictable and transient. A few cases of intravascular hemolysis have been reported; hypersensitivity reactions are very rare. WinRho anti-D has been shown in both clinical trials and postmarketing surveillance to be safe and effective in the treatment of idiopathic thrombocytopenic purpura (ITP) and in the prevention of Rh isoimmunization.

Immunologic interference from sequential administration of live attenuated alphavirus vaccines.

Two different human vaccine trials examined interference arising from sequential administration of vaccines against heterologous alphaviruses. The first trial indicated that persons previously vaccinated against Venezuelan equine encephalitis virus (VEEV) exhibited poor neutralizing antibody responses to a live attenuated chikungunya virus (CHIKV) vaccine (46% response rate). The second trial prospectively examined neutralizing antibody responses to live attenuated VEEV vaccine in persons previously inoculated with either CHIKV vaccine or placebo. Following seroconversion to CHIKV, CHIKV vaccine recipients' geometric mean titers (GMTs) to VEEV by 80% plaque-reduction neutralization titration never exceeded 10, compared with a peak GMT of 95 after VEEV vaccination for alphavirus-naive volunteers who initially received placebo (P < .003). ELISA antibody responses demonstrated cross-reactive IgG to VEEV after primary CHIKV immunization and then an anamnestic response upon subsequent VEEV vaccination. These data indicate that preexisting alphavirus immunity in humans interferes with subsequent neutralizing antibody response to a live attenuated, heterologous vaccine.

Immunologic effects of anti-D (WinRho-SD) in children with immune thrombocytopenic purpura.

Intravenous immunoglobulin (IVIG) is an effective treatment for immune thrombocytopenic purpura (ITP) that induces transient blockade of the reticuloendothelial system (RES) with additional effects including alteration of T lymphocyte subsets and suppression of in vitro T lymphocyte proliferation. As anti-D also is an effective treatment for ITP, we investigated its in vitro and in vivo immunologic effects. The in vitro effects of various agents used in ITP therapy were compared using T lymphocyte proliferation assays. Anti-D caused significantly less inhibition than IVIG or dexamethasone, but non-specific protein was as suppressive as IVIG. Six children with chronic ITP were studied following anti-D administration. Patients received a single dose of anti-D (WinRho-SD, 50 microg/kg i.v. over 5 min) and were studied on day 0, day 7, and 1 month later. Anti-D did not affect T lymphocyte subsets including the T cell receptor variable beta repertoire, in vitro T lymphocyte proliferation to mitogens, recall antigens, or interleukin-2, in vitro IgG synthesis induced by pokeweed mitogen, or T lymphocyte cytokine mRNA levels. We conclude that anti-D has no demonstrable in vitro or in vivo effects on lymphocyte enumeration or function, and therefore likely is effective in the treatment of ITP primarily through RES blockade.

Infant immunization with pneumococcal CRM197 vaccines: effect of saccharide size on immunogenicity and interactions with simultaneously administered vaccines.

Six pentavalent pneumococcal conjugate vaccines (Pn-CRM197) were evaluated among 400 infants. The vaccines differed in saccharide chain length (oligosaccharide [OS] or polysaccharide [PS]) and saccharide quantity (0.5, 2, or 5 microg). Subjects were randomized into groups 1-6 (Pn-CRM197 recipients) or 7 (controls) for immunization at 2, 4, and 6 months of age. Pn-CRM197 were well tolerated and elicited mean antibody concentrations that exceeded those in controls for all 5 capsular serotypes. PS formulations were generally more immunogenic than their OS counterparts. For PS vaccines, a dose-response was documented (5 microg > 2 microg > 0.5 microg), but the differences between the 5- and 2-microg formulations were insignificant. The mean anti-PRP antibody concentration was significantly higher among Pn-CRM197 recipients. It is concluded that PS vaccines are more immunogenic than OS vaccines. The improved immunogenicity from Haemophilus type b oligosaccharide conjugate (HbOC) vaccine when given with Pn-CRM197 suggests that a decreased dose of HbOC vaccine may be sufficient to elicit protection.

Comparison of the safety and immunogenicity of a pneumococcal conjugate with a licensed polysaccharide vaccine in human immunodeficiency virus and non-human immunodeficiency virus-infected children.

OBJECTIVE: To compare the safety and immunogenicity of a 5-valent pneumococcal conjugate vaccine to a licensed 23-valent polysaccharide pneumococcal vaccine in HIV-infected and non-HIV-infected children > or = 2 years old. METHODS: Thirty HIV-infected and 30 non-HIV-infected children > or = 2 years old were randomized to receive either a 5-valent pneumococcal conjugate vaccine (PCV) or a 23-valent pneumococcal polysaccharide vaccine (PPV) intramuscularly. Children who received PCV initially were given PPV after 6 weeks. Sera were obtained before and at 6 and 12 weeks after the first vaccination to determine IgG pneumococcal antibody titers by enzyme-linked immunosorbent assay to the 5 serotypes represented in the PCV. RESULTS: Both vaccines were well-tolerated with no significant differences in the rates of fever (0 to 14%) or local reactions (0 to 40%) noted between PCV and PPV recipients. Pre-first vaccination geometric mean antibody titers (combined PCV and PPV recipients) to 3 of the 5 pneumococcal types tested were significantly lower in HIV-infected than in non-HIV-infected children (in microgram/ml: type 6B, 0.179 vs. 0.565; type 14, 0.026 vs. 0.060; type 23F, 0.025 vs. 0.119, respectively; P < 0.05). Fewer > or = 4-fold titer rises were observed in HIV vs. non-HIV-infected children whether they received PCV initially (60% vs. 79%, P < 0.05) or PPV (31% vs. 59%, P < 0.05). Also PCV elicited more > or = 4-fold titer rises compared with PPV in HIV-infected (60% vs. 31%, P < 0.05) and non-HIV-infected (79% vs. 59%, P < 0.05) children. No consistent antibody-boosting effect was noted in subjects who received PPV after PCV. CONCLUSIONS: We conclude that antibody responses to natural infection, PCV and particularly PPV are poorer in HIV-infected than in non-HIV-infected children. PCV is as safe as and more immunogenic than the currently licensed PPV among HIV-infected and non-HIV-infected children.

Pentavalent pneumococcal oligosaccharide conjugate vaccine PncCRM is well-tolerated and able to induce an antibody response in infants.

BACKGROUND: The emergence of resistant pneumococci makes the treatment of pneumococcal diseases difficult. The currently available polysaccharide vaccines have very limited efficacy in young children. The immunogenicity can be improved by covalent coupling to protein carriers as has been shown with Haemophilus influenzae type b. METHODS: Thirty healthy infants were immunized with a pneumococcal conjugate vaccine at 2, 4 and 6 months of age. Oligosaccharides were derived from capsular polysaccharides of types 6B, 14, 18C, 19F and 23F and conjugated to the nontoxic mutant diphtheria toxin CRM197. The final vaccine was a mixture of these conjugates, containing 10 micrograms of each oligosaccharide. The infants received simultaneously H. influenzae type b oligosaccharide-CRM197 conjugate vaccine. Serum samples were taken before each dose and 1 month after the third dose. Control material was composed of 25 serum samples taken from children of the same age without pneumococcal vaccination. Enzyme-linked immunosorbent assay was used to measure serum IgG anti-pneumococcal polysaccharide concentrations and radioimmunoassay for the serum Ig anti-H. influenzae type b concentrations. RESULTS: PncCRM vaccine was well-tolerated. Pneumococcal type 18C induced a significant antibody increase after the first dose, whereas the other five oligosaccharides, including H. influenzae type b oligosaccharides, induced an increase after the second or third dose. The specific IgG concentrations at 7 months of age were significantly higher among the vaccinated infants than in the controls for all the five pneumococcal types. CONCLUSIONS: Pneumococcal oligosaccharide-CRM197 conjugate vaccine is able to induce an IgG serum response in infants and anti-pneumococcal antibody concentrations were significantly higher than in controls of same age.

Purified fusion protein vaccine protects against lower respiratory tract illness during respiratory syncytial virus season in children with cystic fibrosis.

OBJECTIVE: To test in a double blind, placebo-controlled study a purified fusion protein (PFP-2) vaccine against respiratory syncytial virus (RSV) in RSV-seropositive children with cystic fibrosis (CF). METHODS: Seventeen CF children, mean age 4.5 years, received PFP-2 vaccine and 17 CF children, mean age 5.8 years, received a saline vaccine. At enrollment the Shwachman clinical score, Brasfield radiographic score, oxygen saturation (SpO2), anthropometric indices and other variables were recorded. After vaccination the reactions were assessed daily for 7 days. During the RSV season weekly telephone interviews were performed and children with an acute respiratory illness were evaluated and cultured for RSV. Serum was drawn before vaccination, 1 month after vaccination and at the end of the RSV season and tested for antibodies to RSV. RESULTS: Other than age the baseline measurements at enrollment were similar between groups. The PFP-2 vaccine produced mild local reactions and induced a significant neutralizing antibody response in two-thirds of the vaccinees and a significant enzyme-linked immunosorbent assay-fusion glycoprotein antibody response in nearly all the PFP-2 vaccinees. Vaccine-enhanced disease was not observed in PFP-2 vaccines infected with RSV. Protection against RSV infection was not observed; however, a significant reduction (t test, P < 0.01) in mean number of lower respiratory tract illnesses (0.8 vs. 2.1), antibiotic courses (2.2 vs 4.5) and days ill (30.5 vs. 67) occurred among RSV-infected PFP-2 vaccinees. CONCLUSIONS: Efficacy of the PFP-2 vaccine against lower respiratory tract illness during the RSV season was shown in RSV-seropositive children with CF.

Limited potential for mosquito transmission of a live, attenuated chikungunya virus vaccine.

Studies were conducted to determine the potential for transmission of a live, attenuated chikungunya (CHIK) virus vaccine by orally exposed or virus-inoculated mosquitoes. The vaccine (CHIK 181/clone 25) replicated in and was transmitted by female Aedes albopictus and Ae. aegypti after intrathoracic inoculation. Mosquitoes also became infected with the vaccine after ingesting virus from either a blood-soaked cotton pledget or a viremic monkey. However, because of the low viremias produced in inoculated humans, it is unlikely that mosquitoes would become infected by feeding on a person inoculated with the live, attenuated CHIK vaccine. Although the vaccine was transmitted by mosquitoes after intrathoracic inoculation, there was no evidence of reversion to a virulent phenotype.

Strenuous exercise simulating hepatic injury during vaccine trials.

Three healthy young men participating in phase 1 clinical vaccine trials had unexplained increases in their serum transaminase levels. Retrospective analysis indicated that these volunteers had participated in strenuous physical training 2-5 days prior to the noted elevations. The pattern of serum enzyme elevations, initially thought to be consistent with hepatic injury, were associated with parallel increases in creatine phosphokinase. One individual consented to repeat his exercise regimen. This was followed by a recurrence of the same pattern of increases in serum enzymes, including creatine phosphokinase. Thus, in trials where serum enzymes will be measured, it may be prudent to encourage subjects to refrain from increasing their activity above that which they normally perform.

Preparation of an attenuated dengue 4 (341750 Carib) virus vaccine. II. Safety and immunogenicity in humans.

To determine safety and immunogenicity, a single 0.5 ml dose of a monovalent live-attenuated dengue (DEN) 4 (341750 Carib) vaccine was given sc to 3 groups of flavivirus nonimmune volunteers in increasing concentrations. Two recipients received 10(3) plaque forming units (PFU)/dose (1:100 dilution of stock vaccine). One remained asymptomatic, but became viremic between days 12 and 15, experienced a mild elevation of temperature (37.4 degrees C), and developed DEN-4 specific antibody. Neither recipient of the 10(4) PFU became infected. Eight volunteers then received undiluted vaccine (10(5) PFU). Viremia and antibody (neutralizing, hemagglutination inhibition, and IgM) developed in 5 of the 8 (63%). These 5 volunteers also developed a scarcely noticeable macular, blanching rash and minimal temperature elevations (37.3, 38.1, 37, 37.9, and 37.9 degrees C). Clinically insignificant decreases in total white blood cell, lymphocyte, and polymorphonuclear cell counts and an elevation in mononuclear cell counts occurred in association with viremia. This vaccine is safe, reasonably immunogenic, and suitable for further evaluation.