The safety and efficacy of live attenuated influenza vaccine in young children with asthma or prior wheezing.

In the European Union and Canada, an Ann Arbor strain live attenuated influenza vaccine (LAIV) is approved for use in children aged 2-17 years, including those with mild to moderate asthma or prior wheezing. The safety and efficacy of LAIV versus trivalent inactivated influenza vaccine (TIV) in children with asthma aged 6-17 years have been demonstrated. However, few data are available for children younger than 6 years of age with asthma or prior wheezing. Safety and efficacy data were collected for children aged 2-5 years with asthma or prior wheezing from two randomized, multinational trials of LAIV and TIV (N = 1,940). Wheezing, lower respiratory illness, and hospitalization were not significantly increased among children receiving LAIV compared with TIV. Increased upper respiratory symptoms and irritability were observed among LAIV recipients (p < 0.05). Relative efficacies were consistent with the results observed in the overall study populations, which demonstrated fewer cases of culture-confirmed influenza illness in LAIV compared with TIV recipients. Study results support the safety and efficacy of LAIV among children aged 2-17 years with mild to moderate asthma or a history of wheezing. Data regarding LAIV use are limited among individuals with severe asthma or active wheezing within the 7 days before vaccination.

Translational research on vaccines: influenza as an example.

Influenza vaccine development is reviewed as an example of ongoing translational research, which is moving fundamental advances in biology into useful products. The types of new influenza vaccines span the gamut of modern biology research and include new methods of vaccine production (tissue culture compared with egg-produced vaccine). New vaccines being studied include recombinant proteins, polynucleotide vaccines, conjugate vaccines, peptides, expression vectors, and live attenuated vaccines; new adjuvants are being explored to reduce the quantity of antigen needed. The benefits of using reverse genetics are explored. The limits of translational research for predicting clinical results after wide use of vaccines are discussed, including one example of "overinterpretation" of data; some questions should be left to phase IV experience to answer. The pipeline for new influenza vaccines is robust, and recent investment by government and industry in newer vaccines will bring several new products to clinical use.

Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus-infected and noninfected children.

OBJECTIVE: To assess the safety of live, attenuated influenza vaccine (LAIV) administered to relatively asymptomatic or mildly symptomatic HIV-infected children and non-HIV-infected children. METHODS: Twenty-five non-HIV and 24 HIV-infected children (CDC Class N or A1,2) were enrolled into this double blind, placebo-controlled study. Children were randomized within each HIV status group to one of two dosing regimens: Regimen 1, Dose 1 = LAIV, Dose 2 = placebo, Dose 3 = LAIV; or Regimen 2, Dose 1 = placebo, Dose 2 = LAIV, Dose 3 = LAIV. Study doses were separated by 28 to 35 days. Reactogenicity events within 10 days and adverse events within 28 to 35 days after each study dose were recorded. Blood HIV RNA concentrations, CD4 counts and CD4% were measured throughout the study on HIV-infected children. Quantitative influenza cultures were performed on nasal aspirates collected periodically from all children up to 28 to 35 days after each study dose. Influenza isolates were assessed for retention of the temperature-sensitive phenotype. Serum influenza HAI antibodies were measured before and after each LAIV vaccination. RESULTS: No significant differences were found in rates of reactogenicity events and vaccine-related adverse events after placebo or the first dose of LAIV within each HIV status group, nor were differences found between HIV-infected and HIV-uninfected children after each dose of LAIV. Overall none of the HIV-infected children experienced a significant LAIV-related serious adverse event or influenza-like illness, making the one sided 95% CI of such a serious event occurring after LAIV 0 to 12%. No significant changes in geometric mean HIV RNA concentrations, CD4 counts or CD4% or prolonged or increased quantity of LAIV virus shedding occurred in HIV-infected children after receiving either dose of LAIV. All recovered influenza isolates retained the temperature-sensitive phenotype. After two doses of LAIV, 83% of the non-HIV-infected and 77% of the HIV-infected children had a > or = 4-fold rise in influenza antibody to at least one of the three LAIV strains. CONCLUSION: If relatively healthy HIV-infected children become exposed to LAIV inadvertently, then serious adverse outcomes would not be expected to occur frequently.

HIV type 1 vaccine-induced T cell memory and cytotoxic T lymphocyte responses in HIV type 1-uninfected volunteers.

T cell memory to human immunodeficiency virus type 1 (HIV-1) antigens and anti-HIV-1 cytotoxic T lymphocyte (CTL) activity were assessed after administration of live canarypox virus (ALVAC) expressing HIV-1 env, gag, and protease (vCP205) vaccine given alone, vCP205 given with SF-2 recombinant gp120 (rgp120) vaccine, and placebos at 0, 1, 3, and 6 months. Healthy, HIV-1-uninfected subjects reporting high-risk and low-risk behavior for HIV-1 were enrolled. Anti-HIV-1 Env CD8(+) CTLs (HIV-1(MN) and/or HIV-1 subtype B and C primary isolate sequences) were detected in 12 (60%) and anti-HIV-1 Gag CD8(+) CTLs in 7 (35%) of the 20 vCP205 vaccine recipients tested by CTL assay 3.5 months after the final immunization. Fourteen days after the fourth immunization, lymphocyte proliferation in response to HIV-1 Gag antigen was detected in 14 (48%) of 29 vCP205 vaccine recipients, but secreted cytokine levels to HIV-1 Gag antigen were not above unstimulated levels. Coadministration of SF-2 rgp120 vaccine with vCP205 vaccine enhanced lymphocyte proliferation in response to HIV-1 envelope glycoprotein and broadened the envelope-stimulated cytokine secretion pattern, so that it consisted of both Th1 and Th2 cytokines compared with only interferon gamma (IFN-gamma) after vCP205 vaccine given alone. There was a possible association between HIV-1 envelope glycoprotein-stimulated interleukin 2 secretion and CD8(+) CTLs against HIV-1 envelope glycoprotein, and an inverse relation between lymphocyte proliferation and CTLs against HIV-1 Gag antigens. Thus, a durable anti-HIV-1 CD8(+) CTL response was detected after immunization with the live canarypox virus vaccine and preexisting helper T cell memory responses did not necessarily predict later CD8(+) CTL activity.

Cost-effectiveness analysis of an intranasal influenza vaccine for the prevention of influenza in healthy children.

OBJECTIVE: Intranasal influenza vaccine has proven clinical efficacy and may be better tolerated by young children and their families than an injectable vaccine. This study determined the potential cost-effectiveness (CE) of an intranasal influenza vaccine among healthy children. METHODS: We conducted a CE analysis of data collected between 1996 and 1998 during a prospective 2-year efficacy trial of intranasal influenza vaccine, supplemented with data from the literature. The CE analysis included both direct and indirect costs. We enrolled 1602 healthy children aged 15 to 71 months in year 1, 1358 of whom were enrolled in year 2. One or 2 doses of intranasal influenza vaccine or placebo were administered to measure the cost per febrile influenza-like illness (ILI) day avoided. RESULTS: During the 2-year study period, vaccinated children had an average of 1.2 fewer ILI fever days/child than unvaccinated children. In an individual-based vaccine delivery scenario with vaccine given twice in the first year and once each year thereafter at an assumed base case total cost of $20 for the vaccine and its administration (ie, per dose), CE was approximately $30/febrile ILI day avoided. CE ranged from $10 to $69/febrile ILI day avoided at $10 to $40/dose, respectively. In a group-based delivery scenario, vaccination was cost saving compared with placebo and remained so if vaccine cost was <$28 (the break-even price per dose). In the individual-based scenario, vaccination was cost saving if vaccine cost was <$5. In this scenario, nearly half of lost productivity in the vaccine group was attributable to vaccine visits, which overshadowed the relatively modest savings in ILI-associated costs averted. CONCLUSIONS: Routine use of intranasal influenza vaccine among healthy children may be cost-effective and may be maximized by using group-based vaccination approaches. cost-effectiveness, influenza, vaccine, children.

Canarypox vaccines induce antigen-specific human gammadelta T cells capable of interferon-gamma production.

Induction of human gammadelta T cells was investigated in subjects who were vaccinated with live recombinant canarypox virus expressing human immunodeficiency virus (HIV) proteins or soluble MN rgp120. Both canarypox and rgp120 induced antigen-specific lymphoproliferative and interferon (IFN)-gamma responses. However, only canarypox vaccination induced increased gammadelta T cell responses detectable after secondary in vitro expansion (P<.02). These enhanced gammadelta T cell responses were specific for canarypox but not HIV antigens. Canarypox-specific gammadelta T cells were predominantly Vgamma9(+) and produced intracellular and secreted IFN-gamma. gammadelta T cell lines generated from canarypox vaccinees responded to canarypox antigens but not to mycobacterial antigens shown previously to induce bacille Calmette-Guérin-specific gammadelta T cells. Furthermore, canarypox vaccinations were associated with significantly higher NK cell expansions (P=.02). Increased IFN-gamma production by gammadelta T and NK cells could enhance the induction of protective type 1 memory immunity. Thus, stimulation of gammadelta T cells might be an important feature of live vaccines.

Safety and immunogenicity of a canarypox-vectored human immunodeficiency virus Type 1 vaccine with or without gp120: a phase 2 study in higher- and lower-risk volunteers.

Live attenuated viral vectors that express human immunodeficiency virus (HIV) antigens are being developed as potential vaccines to prevent HIV infection. The first phase 2 trial with a canarypox vector (vCP205, which expresses gp120, p55, and protease) was conducted in 435 volunteers with and without gp120 boosting, to expand the safety database and to compare the immunogenicity of the vector in volunteers who were at higher risk with that in volunteers at lower risk for HIV infection. Neutralizing antibodies to the MN strain were stimulated in 94% of volunteers given vCP205 plus gp120 and in 56% of volunteers given vCP205 alone. CD8(+) cytotoxic T lymphocyte cells developed at some time point in 33% of volunteers given vCP205, with or without gp120. Phase 3 field trials with these or similar vaccines are needed, to determine whether efficacy in preventing HIV infection or in slowing disease progression among vaccinees who become infected is associated with the level and types of immune responses that were induced by the vaccines in this study.

Immunoregulatory role of secreted glycoprotein G from respiratory syncytial virus.

The secretory glycoprotein (Gs) of respiratory syncytial virus (RSV) was enriched and investigated for its effects on T cells specific for RSV and unrelated antigens. Gs exhibited a dose dependent suppression of lymphoproliferative responses in peripheral blood mononuclear cells (PBMCs), specific for mycobacterial lysates or tetanus toxoid. However, Gs did not inhibit live RSV specific T cell responses. These results suggest that Gs may suppress immune response to unrelated antigens, but should not interfere with the overall development of RSV specific immunity.

Cytokine responses to human immunodeficiency virus type 1 (HIV-1) induced by immunization with live recombinant canarypox virus vaccine expressing HIV-1 genes boosted by HIV-1(SF-2) recombinant GP120.

Vaccine-induced T-cell memory for human immunodeficiency virus type 1 (HIV-1) was assessed by measuring HIV-1 antigen-stimulated cytokine secretion in 72 HIV-1-uninfected subjects, of whom 52 received live recombinant canarypox virus vaccine expressing HIV-1 env, gag, and protease gene products (vCP205) with or without HIV-1(SF-2) recombinant gp120 (SF-2 rgp120) subunit vaccine, and 20 the control. The vCP205 vaccine induced secretion of the Th1 cytokine, interferon-gamma, by peripheral blood mononuclear cells (PBMC) after in vitro stimulation with HIV-1 p24 and envelope glycoprotein. Immunization schedules with both vCP205 and SF-2 rgp120 subunit vaccines induced secretion of Th1 and Th2 cytokines by PBMC to HIV-1 envelope glycoprotein. Hence, vCP205 and SF-2 rgp120 subunit vaccines given together and in a prime-boost sequence appeared to induce a broader cytokine response pattern than vCP205 vaccine given alone.

Safety, efficacy and effectiveness of cold-adapted, live, attenuated, trivalent, intranasal influenza vaccine in adults and children.

Studies in children and adults revealed cold-adapted, live, attenuated, trivalent, intranasal influenza vaccine (CAIV-T) to be well accepted, well tolerated and highly protective against culture-confirmed influenza, and to provide significant health benefits. A 2 year, multicentre, double-blind, placebo-controlled efficacy field trial of CAIV-T in children aged 15-71 months with annual re-immunization revealed the vaccine to be highly protective against culture-confirmed influenza. Vaccine induced serum and secretory antibodies in vaccinated children. Overall, during 2 years of study, vaccine was 92% protective against culture-confirmed influenza. During the second year of study the vaccine was 86% protective against influenza A/Sydney/5/97-like virus, a significantly drifted strain not well matched to the vaccine. Antibody studies on children given CAIV-T revealed that high titres of cross-reacting antibodies to influenza A/Sydney/5/97 were induced with vaccination by live attenuated influenza A/Wuhan/359/95-like vaccine. Effectiveness measures revealed significant reductions in febrile illness (21% reduction in year 1, 19% reduction in year 2), febrile otitis media (33% reduction in year 1, 16% reduction in year 2) and associated antibiotic use among vaccinated children compared with placebo recipients. In adults, vaccination with CAIV-T resulted in protection during experimental challenge with virulent wild-type viruses. An effectiveness trial in adults demonstrated significant benefits of CAIV-T vaccine (28% reduction in days of missed work for febrile upper respiratory illness days with associated 45% reduction in days taking antibiotics). General use of CAIV-T has the potential to significantly reduce the impact of influenza in children and adults.

Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus vaccine candidate in infancy.

A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.

Cytokine profiles in seronegative volunteers immunized with a recombinant canarypox and gp120 prime-boost HIV-1 vaccine. NIAID AIDS Vaccine Evaluation Group.

OBJECTIVES: To study memory T cell proliferative responses and cytokine profiles induced in HIV-1 seronegative volunteers immunized with a live recombinant canarypox vector expressing HIV-1 antigens (ALVAC-HIV) and boosted with a recombinant gp120 subunit vaccine. DESIGN: HIV-specific T cell proliferative responses and cytokines were measured 2 weeks after vaccination. Cytokines secreted by T helper 1 cells (Th1) [interleukin (IL)-2 and interferon-gamma (IFN-gamma)] and T helper 2 (Th2) cells (IL-4, IL-5, IL-6, and IL-10) were assessed both at the mRNA and the protein level. METHODS: Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with HIV antigens. Subsequently, T cell proliferation was measured in a standard lymphoproliferation assay; secreted cytokines were measured using an enzyme-linked immunosorbent assay and upregulation of cytokine mRNA was measured using reverse transcriptase polymerase chain reaction. RESULTS: All individuals who had received ALVAC-HIV followed by the protein vaccine exhibited HIV-1-specific T cell proliferative responses. Moreover, the PBMC of all prime-boost vaccinated individuals produced detectable IFN-gamma and IL-10 in response to stimulation with HIV-1 envelope glycoprotein antigens; 83% also had detectable levels of IL-2 and IL-6, 71% had detectable levels of IL-4, and 86% had detectable levels of IL-5. CONCLUSIONS: These data indicate that this vaccination regimen was inducing both Th1- and Th2-type responses to HIV-1 envelope antigens. This prime-boost vaccination approach elicited T cell help for the generation of cytotoxic T lymphocyte responses as well as help for antibody production and so promises to generate a broad HIV-1-specific immune response.

Mucosal bacille calmette-Guérin vaccination of humans inhibits delayed-type hypersensitivity to purified protein derivative but induces mycobacteria-specific interferon-gamma responses.

We conducted a placebo-controlled, double-dose-escalation trial of oral bacille Calmette-Guérin (BCG) vaccination in 48 healthy volunteers. Seven of 32 BCG recipients became purified protein derivative (PPD)-positive after dose 1, and only 1 remained positive after dose 2, which suggests that oral BCG has inhibitory effects on delayed-type hypersensitivity (DTH) responses. Ten of the original placebo recipients and 11 oral BCG recipients were recruited to return for an intradermal BCG booster vaccination. Five of 10 original placebo recipients developed PPD responses >/=10 mm, but none of 11 oral BCG recipients developed PPD induration after they received an intradermal BCG booster (P<.05; Fisher's exact test). These results document persistent inhibitory effects of oral BCG vaccination on mycobacteria-specific DTH responses. Despite inhibition of DTH, oral BCG induced significant increases in mycobacteria-specific interferon (IFN)-gamma responses in peripheral blood mononuclear cells. More detailed studies of cytokine and homing molecule expression indicated that differential mucosal versus cutaneous trafficking may explain the dissociation between IFN-gamma and DTH responses.

Estimation of the efficacy of live, attenuated influenza vaccine from a two-year, multi-center vaccine trial: implications for influenza epidemic control.

The authors provide an analysis of data from a two-year (1996-1998), multicenter (ten US cities), double-blinded, placebo-controlled influenza vaccine trial in children. The vaccine was the trivalent cold-adapted influenza vaccine. Estimates are made of the vaccine efficacy for susceptibility to culture-confirmed influenza (VE(S)) while taking inter-center variability in the risk of infection into account. Our overall estimate of VE(S) against influenza is 0.92 (95% confidence interval (CI) 0.89-0.94). In addition, for the second year, although the vaccine contained antigen for A/Wuhan-like (H3N2), the estimated VE(S) for epidemic variant A/Sydney-like (H3N2) was 0.89 (95% CI 0.81-0.94). Thus, the vaccine showed a high degree of protection against a variant not closely matched to the vaccine antigen. With regard to natural immunity, an influenza A infection in the first year reduces the estimated risk of an influenza A infection in the second year by a factor of 0.88 (95% CI 0.21-0.98). When comparing year 1 to year 2, there is a negative correlation of -0.50 in the center-specific attack rates in the placebo groups. This is consistent with the theory that natural immunity provides overall community protection to children. The authors argue that mass vaccination of 70% of the children with the cold-adapted influenza vaccine could provide substantial protection to the community at large.

Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine.

The authors conducted a 2-year, multicenter, double-blind, placebo-controlled efficacy field trial of live, attenuated, cold-adapted, trivalent influenza vaccine administered by nasal spray to children 15-71 months old. Overall, vaccine was 92% efficacious at preventing culture-confirmed infection by influenza A/H3N2 and influenza B. Because influenza A/H1N1 did not cause disease during the years in which this study was conducted, the authors sought to determine vaccine efficacy and correlates of immune protection against experimental challenge with 107 TCID50 of attenuated H1N1 (vaccine strain) by intranasal spray. Prechallenge assessments included serum hemaglutination-inhibiting (HAI) antibody and nasal wash IgA antibody to H1N1. Vaccine was 83% efficacious (95% confidence interval, 60%-93%) at preventing shedding of H1N1 virus after challenge. Any serum HAI antibody or any nasal wash IgA antibody was correlated with significant protection from H1N1 infection as indicated by vaccine-virus shedding, and high efficacy against H1N1 challenge was demonstrated.

Comparison of the safety, vaccine virus shedding, and immunogenicity of influenza virus vaccine, trivalent, types A and B, live cold-adapted, administered to human immunodeficiency virus (HIV)-infected and non-HIV-infected adults.

Fifty-seven human immunodeficiency virus (HIV)-infected (CDC class A1-2) and 54 non-HIV-infected adults, not prescreened for influenza susceptibility, were randomized to receive trivalent live attenuated influenza vaccine (LAIV) or placebo intranasally. LAIV was safe and well tolerated with no serious adverse events attributable to vaccine. Reactogenicity rates were similar in LAIV and placebo recipients except that runny nose/nasal congestion was significantly more common in LAIV recipients regardless of HIV status. No prolonged shedding of LAIV was observed in HIV-infected participants. HIV RNA levels were not increased and CD4 counts were not decreased in HIV-infected LAIV recipients compared with placebo recipients after immunization. Shedding of LAIV and increases in antibody titers were infrequent, consistent with prior experience in unscreened adults. The data suggest that inadvertent vaccination with LAIV in relatively asymptomatic HIV-infected adults would not be associated with frequent significant adverse events.

Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine.

OBJECTIVE: To determine the safety, immunogenicity, and efficacy of revaccination of children with live attenuated influenza vaccine. STUDY DESIGN: A 2-year multicenter, double-blind, placebo-controlled, efficacy field trial of live attenuated, cold-adapted trivalent influenza vaccine administered by nasal spray to children. This report summarizes year 2 results, a year in which the epidemic strain of influenza A/Sydney was not well matched to the vaccine strains. Each year, vaccine strains were antigenically equivalent to the contemporary inactivated influenza vaccine. In year 2, a single intranasal revaccination was administered. Active surveillance for influenza was conducted during the influenza season by means of viral cultures. Influenza cases were defined as illnesses with wild-type influenza virus isolated from respiratory secretions. RESULTS: In year 2, 1358 (85%) children, 26 to 85 months of age, returned for revaccination. The intranasal vaccine was easily accepted, well tolerated, and immunogenic. Revaccination resulted in 82% to 100% of the vaccinated children in a subset studied for immunogenicity being seropositive as compared with 26% to 65% of placebo recipients, depending on the influenza strain tested. No serious adverse events were associated with the vaccine. In addition to the strains in the vaccine, antibody was induced to the variant strain A/Sydney/H3N2. In year 2, influenza A/Sydney/H3N2, a variant not contained in the vaccine, caused 66 of 70 cases of influenza A; nonetheless, intranasal vaccine was 86% efficacious in preventing A/Sydney influenza. Eight cases of lower respiratory tract disease were associated with A/Sydney influenza; all cases were in the placebo group. CONCLUSIONS: This live attenuated, cold-adapted influenza vaccine was safe, immunogenic, and efficacious against influenza A/H3N2 (including a variant, A/Sydney, not contained in the vaccine) and influenza B. The characteristics of this vaccine make it suitable for routine use in children to prevent influenza.

Vaccine-induced cytotoxic T lymphocytes against human immunodeficiency virus type 1 using two complementary in vitro stimulation strategies.

CD8+ cytotoxic T lymphocytes (CTL) against human immunodeficiency virus type 1 (HIV-1) induced by candidate HIV-1 vaccines may be a mechanism of immune protection against HIV-1 infection. We measured in vitro inducible CD8+ and CD4+ CTL using two in vitro effector cell stimulation strategies. Peripheral blood mononuclear cells (PBMC) for CTL assay were obtained after the third and/or fourth immunization timepoints from 23 healthy, uninfected adult volunteers, of whom 19 received a canarypox virus vaccine expressing HIV-1 env, gag, pol, nef and protease gene products (vCP300) with or without injections of HIV-1(SF-2) rgp120 subunit vaccine and four subjects received only control injections. CD8+ CTL activity was detected employing the two in vitro stimulation strategies against one or more HIV-1 antigens in 15 (79%) of 19 HIV-1 vaccine recipients on at least one occasion and repeatedly against the same antigen in 8 (42%). Canarypox virus-based HIV-1 vaccines represent a step forward in HIV-1 vaccine development.