Vaccine-related Severe Adverse Events Research Articles

Safety and immunogenicity of the live-attenuated hRVFV-4s vaccine against Rift Valley fever in healthy adults: a dose-escalation, placebo-controlled, first-in-human, phase 1 randomised clinical trial

Rift Valley fever virus, a pathogen to ruminants, camelids, and humans, is an emerging mosquito-borne bunyavirus currently endemic to Africa and the Arabian Peninsula. Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available. Here we assessed the safety, tolerability, and immunogenicity of a next-generation, four-segmented, live-attenuated vaccine candidate, referred to as hRVFV-4s, in humans. A first-in-human, single-centre, randomised, double-blind, placebo-controlled trial was done in Belgium in which a single dose of hRVFV-4s was administered to healthy volunteers aged 18-45 years. Participants were randomly assigned using an interactive web response system. The study population encompassed 75 participants naive to Rift Valley fever virus infection, divided over three dosage groups (cohorts) of 25 participants each. All participants were followed up until 6 months. Using a staggered dose escalating approach, 20 individuals of each cohort were injected in the deltoid muscle of the non-dominant arm with either 104 (low dose), 105 (medium dose), or 106 (high dose) of 50% tissue culture infectious dose of hRVFV-4s as based on animal data, and five individuals per cohort received formulation buffer as a placebo. Primary outcome measures in the intention-to-treat population were adverse events and tolerability. Secondary outcome measures were vaccine-induced viraemia, vaccine virus shedding, Rift Valley fever virus nucleocapsid antibody responses (with ELISA), and neutralising antibody titres. Furthermore, exploratory objectives included the assessment of cellular immune responses by ELISpot. The trial was registered with the EU Clinical Trials Register, 2022-501460-17-00. Between August and December, 2022, all 75 participants were vaccinated. No serious adverse events or vaccine-related severe adverse events were reported. Pain at the injection site (51 [85%] of 60 participants) was most frequently reported as solicited local adverse event, and headache (28 [47%] of 60) and fatigue (28 [47%] of 60) as solicited systemic adverse events in the active group. No vaccine virus RNA was detected in any of the blood, saliva, urine, or semen samples. Rift Valley fever virus nucleocapsid antibody responses were detected in most participants who were vaccinated with hRVFV-4s (43 [72%] of 60 on day 14) irrespective of the administered dose. In contrast, a clear dose-response relationship was observed for neutralising antibodies on day 28 with four (20%) of 20 participants responding in the low-dose group, 13 (65%) of 20 responding in the medium-dose group, and all participants (20 [100%] of 20) responding in the high-dose group. Consistent with the antibody responses, cellular immune responses against the nucleocapsid protein were detected in all dose groups, whereas a more dose-dependent response was observed for the Gn and Gc surface glycoproteins. Neutralising antibody titres declined over time, whereas nucleocapsid antibody responses remained relatively stable for at least 6 months. The hRVFV-4s vaccine showed a high safety profile and excellent tolerability across all tested dose regimens, eliciting robust immune responses, particularly with the high-dose administration. The findings strongly support further clinical development of this candidate vaccine for human use. The Coalition for Epidemic Preparedness Innovations with support from the EU Horizon 2020 programme.

Safety and immunogenicity of the H56:IC31 tuberculosis vaccine candidate in adults successfully treated for drug-susceptible pulmonary TB: a phase 1 randomized trial.

H56:IC31 is a candidate vaccine against tuberculosis (TB) with the potential to reduce TB recurrence rate. It is thus important for future clinical trials to demonstrate safety and immunogenicity of H56:IC31 in individuals treated for TB. 22 adults confirmed to be Mtb negative (by 2 GeneXpert tests or 2 sputum cultures) after four-five months of TB treatment, and not more than 28 days after completion of TB treatment, were randomized to receive two doses of H56:IC31 (5 mg H56:500 nmol IC31; N=16) or placebo (N=6) 56 days apart. Participants were followed for 420 days for safety and immunogenicity. H56:IC31 vaccination was associated with an acceptable safety profile, consisting mostly of mild self-limited injection site reactions. No serious adverse events, and no vaccine-related severe adverse events, were reported. H56:IC31 induced a CD4+ T-cell response for Ag85B and ESAT-6, with ESAT-6 being immunodominant, which persisted through six months after the last vaccination. There was some evidence of CD8+ T-cell responses for both Ag85B and ESAT-6, but to a lesser extent than CD4+ responses. H56:IC31 was associated with an acceptable safety profile, and induced a predominant CD4+ T-cell response, in adults recently treated for drug-susceptible, uncomplicated pulmonary TB. ClinicalTrials.gov, NCT02375698.

Durability of single-dose HPV vaccination in young Kenyan women: randomized controlled trial 3-year results

Cervical cancer burden is high where prophylactic vaccination and screening coverage are low. We demonstrated in a multicenter randomized, double-blind, controlled trial that single-dose human papillomavirus (HPV) vaccination had high vaccine efficacy (VE) against persistent infection at 18 months in Kenyan women. Here, we report findings of this trial through 3 years of follow-up. Overall, 2,275 healthy women aged 15–20 years were recruited and randomly assigned to receive bivalent (n = 760), nonavalent (n = 758) or control (n = 757) vaccine. The primary outcome was incident-persistent vaccine type-specific cervical HPV infection. The primary evaluation was superiority analysis in the modified intention-to-treat (mITT) HPV 16/18 and HPV 16/18/31/33/45/52/58 cohorts. The trial met its prespecified end points of vaccine type-specific persistent HPV infection. A total of 75 incident-persistent infections were detected in the HPV 16/18 mITT cohort: 2 in the bivalent group, 1 in the nonavalent group and 72 in the control group. Nonavalent VE was 98.8% (95% CI 91.3–99.8%, P < 0.0001) and bivalent VE was 97.5% (95% CI 90.0–99.4%, P < 0.0001). Overall, 89 persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: 5 in the nonavalent group and 84 in the control group; nonavalent VE was 95.5% (95% CI 89.0–98.2%, P < 0.0001). There were no vaccine-related severe adverse events. Three years after vaccination, single-dose HPV vaccination was highly efficacious, safe and conferred durable protection. ClinicalTrials.gov no. NCT03675256.

The Actual Status of Hospitals as COVID-19 Vaccination Clinics in China and Safety Monitoring of Inactivated Vaccine: A Cross-Sectional Study.

The outbreak has had a devastating impact, and efforts are underway to speed up vaccination. The study's objective was to describe the clinical characteristics of the coronavirus disease 2019 (COVID-19) vaccination clinic in the Second People's Hospital of Fujian Province, China. Meanwhile, we monitored all the vaccine recipients to evaluate adverse reactions. A cross-sectional study was done at the COVID-19 Vaccination Clinic, the Second People's Hospital of Fujian Province, China. We systematically collected Clinical data from the COVID-19 vaccination clinic between March 11 and November 11, 2021, including the type of vaccine, number of doses, gender, age, educational level, occupational category, adverse reactions, etc. Investigators will contact vaccine recipients by means of phone call or WeChat message to record the negative responses. Last, this report covers data through 8 mo, so it will be better to Evaluate the Safety of 2 inactivated COVID-19 vaccines from China (BBIBP-CorV [Beijing Institute of Biological Products, Beijing, China] and CoronaVac [Sinovac Life Sciences, Beijing, China]). The results indicated that the Second People's Hospital of Fujian Province received a total of 64,602 COVID-19 vaccines from March 11 to November 11, 2021, including 34,331 (53.14%) first doses, 29,245 (45.27%) second doses, and 1026 (1.59%) third doses. This study found the highest proportion in other personnel (38.69% at the first dose, 38.75% at the second dose, and 2.44% at the third dose), who were mainly retirees. People with higher levels of education are more likely to be vaccinated against COVID-19 during the early stages of vaccine rollout. In terms of age stratification, the highest proportion was found among people aged 18-49 (BBIBP-CorV: first dose 61%, second dose 62.6%, and third dose 76.8%; CoronaVac: first dose 66.1%, double dose 63.6%, and third dose 75.5%), followed by those over 60. The common adverse reactions were mainly local and systemic, and there were some differences between the 2 inactivated vaccines (P < 0.05). This is the first study to analyze the actual status of hospitals as COVID-19 vaccination clinics in China. The hospital has focused on vaccinating citizens and the initial rollout of vaccines to ensure any safety issues are identified. More citizens are willing to vaccinate in hospitals because of the uncertain safety of the available vaccines and adverse reactions. The good news is that vaccine-related severe adverse events have not been found in the hospital vaccination clinic. The Safety of BBIBP-CorV and CoronaVac is relatively high.

Safety monitoring of COVID-19 vaccines – Lessons learned from the 1976 national influenza immunization program about detecting rare vaccine-related severe adverse events in emergency mass-vaccination programs

Safety monitoring of COVID-19 vaccines – Lessons learned from the 1976 national influenza immunization program about detecting rare vaccine-related severe adverse events in emergency mass-vaccination programs

Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial

Results from a previous phase 3 study showed efficacy of the RTS,S/AS01 vaccine against severe and clinical malaria in children (in 11 sites in Africa) during a 3-4-year follow-up. We aimed to investigate malaria incidence up to 7 years postvaccination in three of the sites of the initial study. In the initial phase 3 study, infants aged 6-12 weeks and children aged 5-17 months were randomly assigned (1:1:1) to receive four RTS,S/AS01 doses (four-dose group), three RTS,S/AS01 doses and a comparator dose (three-dose group), or four comparator doses (control group). In this open-label extension study in Korogwe (Tanzania), Kombewa (Kenya), and Nanoro (Burkina Faso), we assessed severe malaria incidences as the primary outcome for 3 additional years (January, 2014, to December, 2016), up to 6 years (younger children) or 7 years (older children) postprimary vaccination in the modified intention-to-treat population (ie, participants who received at least one dose of the study vaccine). As secondary outcomes, we evaluated clinical malaria incidences and serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02207816. We enrolled 1739 older children (aged 5-7 years) and 1345 younger children (aged 3-5 years). During the 3-year extension, 66 severe malaria cases were reported, resulting in severe malaria incidence of 0·004 cases per person-years at risk (PPY; 95% CI 0-0·033) in the four-dose group, 0·007 PPY (0·001-0·052) in the three-dose group, and 0·009 PPY (0·001-0·066) in the control group in the older children category and a vaccine efficacy against severe malaria that did not contribute significantly to the overall efficacy (four-dose group 53·7% [95% CI -13·7 to 81·1], p=0·093; three-dose group 23·3% [-67·1 to 64·8], p=0·50). In younger children, severe malaria incidences were 0·007 PPY (0·001-0·058) in the four-dose group, 0·007 PPY (0·001-0·054) in the three-dose group, and 0·011 PPY (0·001-0·083) in the control group. Vaccine efficacy against severe malaria also did not contribute significantly to the overall efficacy (four-dose group 32·1% [-53·1 to 69·9], p=0·35; three-dose group 37·6% [-44·4 to 73·0], p=0·27). Malaria transmission was still occurring as evidenced by an incidence of clinical malaria ranging from 0·165 PPY to 3·124 PPY across all study groups and sites. In older children, clinical malaria incidence was 1·079 PPY (95% CI 0·152-7·662) in the four-dose group, 1·108 PPY (0·156-7·868) in the three-dose group, and 1·016 PPY (0·14-7·213) in the control group. In younger children, malaria incidence was 1·632 PPY (0·23-11·59), 1·563 PPY (0·22-11·104), and 1·686 PPY (0·237-11·974), respectively. In the older age category in Nanoro, clinical malaria incidence was higher in the four-dose (2·444 PPY; p=0·011) and three-dose (2·411 PPY; p=0·034) groups compared with the control group (1·998 PPY). Three cerebral malaria episodes and five meningitis cases, but no vaccine-related severe adverse events, were reported. Overall, severe malaria incidence was low in all groups, with no evidence of rebound in RTS,S/AS01 recipients, despite an increased incidence of clinical malaria in older children who received RTS,S/AS01 compared with the comparator group in Nanoro. No safety signal was identified. GlaxoSmithKline Biologicals SA.

Immunogenicity and safety of double versus standard dose of the seasonal influenza vaccine in solid-organ transplant recipients: A randomized controlled trial

BackgroundThe use of vaccines with higher doses of antigen is an attractive strategy to improve the immunogenicity of influenza vaccination in transplant recipients. However, the effect of vaccination with a double-dose (DD) containing 30 µg of antigen in this population remains unknown. MethodsWe performed a randomized controlled trial to compare the immunogenicity and safety of DD (30 µg) vs. standard dose (SD, 15 µg) of a trivalent inactivated influenza vaccine in kidney and liver transplant recipients. Immunogenicity was assessed by hemagglutination-inhibition assay. Vaccine response was defined as seroconversion to at least one viral strain 2 weeks after vaccination and seroprotection as a titer ≥40. ResultsSixty-three kidney and 16 liver transplant recipients were enrolled. Forty patients received the DD and 39 the SD vaccine. Overall, 40% of patients in the DD compared to 26% in the SD group (P = 0.174) responded to vaccine. In the DD arm, more patients were seroprotected to all viral strains after vaccination (88% vs 69%, P = 0.048). Post vaccination geometric mean titers of antibodies were 131.9 vs. 89.7 (P = 0.187) for H1N1, 185.4 vs. 138.7 (P = 0.182) for H3N2, and 96.6 vs. 68.8 (P = 0.081) for influenza B with the DD vs. SD. In both groups, most of the adverse events were mild and no vaccine-related severe adverse events were observed. ConclusionDouble-dose influenza vaccine is safe and may increase antibody response in transplant recipients. In this population, DD vaccination could be an alternative when high-dose vaccine is not available. NCT02746783.

MP2-20 FEASIBILITY STUDY OF PERSONALIZED PEPTIDE VACCINATION FOR PLATINUM-BASED CHEMOTHERAPY RESISTANT METASTATIC UPPER TRACT UROTHELIAL CARCINOMA PATIENTS

You have accessJournal of UrologyBladder Cancer: Upper Tract TCC I1 Apr 2015MP2-20 FEASIBILITY STUDY OF PERSONALIZED PEPTIDE VACCINATION FOR PLATINUM-BASED CHEMOTHERAPY RESISTANT METASTATIC UPPER TRACT UROTHELIAL CARCINOMA PATIENTS Shigetaka Suekane, Masanori Noguchi, Kousuke Ueda, Tsukasa Igawa, Tetsuro Sasada, and Kyogo Itoh Shigetaka SuekaneShigetaka Suekane More articles by this author , Masanori NoguchiMasanori Noguchi More articles by this author , Kousuke UedaKousuke Ueda More articles by this author , Tsukasa IgawaTsukasa Igawa More articles by this author , Tetsuro SasadaTetsuro Sasada More articles by this author , and Kyogo ItohKyogo Itoh More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.143AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The prognosis of metastatic upper tract urothelial carcinoma ( UTUC ) patients who failed platinum-based chemotherapy remains very poor. We conducted a feasibility study of personalized peptide vaccine ( PPV ) for platinum-based chemotherapy resistant metastatic UTUC patients to explore cancer vaccine as a new treatment modality. METHODS A total of 34 UTUC patients were enrolled to this study, who were platinum-based chemotherapy resistant metastatic 21 pelvic cancer and 13 ureter cancer. A maximum of four HLA-matched peptides showing higher antigen-specific immunoglobulin G ( IgG ) responses were selected based on measurement of IgG against different cytotoxic T lymphocyte ( CTL ) epitope peptides followed by subcutaneous vaccination. This study protocol was approved by the institutional ethical review boards of Kurume University, and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients before entering this clinical trial. RESULTS There were no vaccine-related severe adverse events of PPV in all patients. Median overall survival ( OS ) time from the first PPV was 13.0 months in platinum-based chemotherapy resistant metastatic UTUC patients. Increased the anti-peptide IgG titer were revealed seventeen patients ( 50.0% ) of thirty-four patients at post 6th vaccination, and sixteen patients ( 100% ) of sixteen patients at post 12th vaccination. Seventeen patients with 12th more PPV showed significantly longer survival than 17 patients with less than 12th PPV (hazard ratio [HR], 4.775, P=0.0015). Peptide-specific immune response at 12th PPV in platinum-based chemotherapy resistant metastatic UTUC patients was favorable biomarker for OS ( P=0.0002 ), regardless of the response at 6th PPV. CONCLUSIONS PPV as a new treatment modality in patients with platinum-based chemotherapy resistant metastatic UTUC is active and well tolerated, improving survival with immune responses. Further large-scale, randomized trials are needed to confirm these results. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e18 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shigetaka Suekane More articles by this author Masanori Noguchi More articles by this author Kousuke Ueda More articles by this author Tsukasa Igawa More articles by this author Tetsuro Sasada More articles by this author Kyogo Itoh More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Abstract P5-01-05: Personalized peptide vaccines in combination with conventional chemo- or endocrine therapy for metastatic breast cancer: A single-arm phase II study

Abstract Background: Immunotherapy using multiple personalized peptide vaccines (PPV) has been reported to be effective for boosting anticancer immunity in patients (pts) with advanced prostate cancer and glioblastoma. The PPVs binding HLA-A2, A24, A3 family and A26 molecules were selected from 31 candidate peptides derived from various tumor associated antigens. Currently, we performed a phase II trial to evaluate the benefit of the PPVs in combination with conventional chemo-or endocrine therapy for pretreated metastatic breast cancer (MBC). Methods: Seventy-one pretreated pts had histologically confirmed measurable MBC and their HLA A molecules matched each of HLA-A2, A24, A26 and A3 family. Pre-vaccination plasma was measured for their IgG levels reactive to each of 31 peptides followed by administration subcutaneously of the four peptides at maximum showing higher levels of IgG in order with schedule of every 1-2 week. The concurrent conventional chemotherapy or endocrine therapy was available for the combination of PPVs. The primary endpoint was anti-tumor immunologic effect and safety, and the secondary endpoints were clinical responses and survival. Levels of IgG reactive to each of the 31 peptides in the pre- and post-treatment plasma at every 6 times of vaccination were measured using LUMNEX system. The CTL responses were simultaneously evaluated using ELISPOT method. Clinical response was evaluated by RECIST criteria. Results: Between May 2009 and December 2012, a total of 71 pts (Luminal-Her2- cases: 39; Her2+cases: 18; Triple negative(TN) cases:14) were enrolled in this study. The median duration of follow-up was 20.7 months. Concurrent chemotherapies (capecitabine, gemcitabine, eribulin, vinorelbine etc.) and endocrine therapies (aromatase inhibitor, toremifen or fulvestrant) were administered to 36 and 24 pts, respectively. Trastuzumab, Laptinib or Bevacizumab was simultaneously used for 13 pts. After 6th vaccination, the IgG reaction and CTL response were identified in 53 of 71 (74.6%) pts and 33 of 63 (52.3%) pts. There were no significant differences between TN cases and the other cases of MBC with regard to immunological humoral and/or cellular responses. No vaccine-related severe adverse events were observed. Clinical response rate of assessable 61 pts was 14.8% (CR 3, PR 6, SD 24, PD 28). The median PFS and OS were 7.6 m and 20.7 m, respectively. In contrast, the PFS and OS of luminal type, Her2 type or TN type were 12, 4.6 or 8.3 m and 24, 15 or 12 m. Conclusions: The phase II PPVs study for MBC demonstrated the promising response and safety, and further studies are essential to identify the clinical benefits of this novel therapy. Clinical trial information: UMIN000001482. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-01-05.

Safety and Immunogenicity of an AS01-adjuvanted Varicella-zoster Virus Subunit Candidate Vaccine Against Herpes Zoster in Adults &gt;=50 Years of Age

An adjuvanted varicella-zoster virus glycoprotein E (gE) subunit vaccine candidate for herpes zoster is in development. In this trial we compared the safety, reactogenicity, and immunogenicity of the vaccine antigen combined with different adjuvant doses. This was a phase II, observer-blind, randomized, multinational study. Adults ≥50 years old were randomized 4:4:2:1 to be vaccinated at months 0 and 2 with gE combined with a higher (AS01B) or lower (AS01E) dose adjuvant, unadjuvanted gE, or saline. Following each dose, solicited events were recorded for 7 days and unsolicited adverse events for 30 days. Serious adverse events were collected for 1 year. Cell-mediated and humoral immune responses were assessed at baseline and following each dose. No vaccine-related severe adverse events were reported. Solicited adverse events were generally mild to moderate and transient. For all gE-based vaccines, pain was the most common local symptom and fatigue the most common general symptom. Immune responses were significantly enhanced by AS01B and AS01E compared to unadjuvanted gE and were significantly stronger for gE/AS01B than for gE/AS01E. AS01 improved the immunogenicity of gE while retaining acceptable safety and reactogenicity profiles. The enhancement of gE-specific cellular and humoral responses was adjuvant dose dependent. NCT00802464.

A phase II study of a personalized peptide vaccination for chemotherapy-resistant advanced pancreatic cancer patients

Pancreatic cancer is one of the most aggressive cancers with a median survival time (MST) of <6 months in chemotherapy-resistant patients. Therefore, the development of novel treatment modalities is needed. In the present study, a phase II study of personalized peptide vaccination (PPV) was conducted, in which vaccine antigens were selected and administered based on the pre-existing IgG responses to 31 different pooled peptides, for 41 chemotherapy-resistant advanced pancreatic cancer patients. No vaccine-related severe adverse events were observed. IgG responses specific to at least one of the vaccine peptides were augmented in 14 of 36 patients (39%) and in 18 of 19 patients (95%) tested after the 5th and 11th vaccination, respectively. MST from the first vaccination was 7.9 months with a 1-year survival rate of 26.8%. Higher serum amyloid A (SAA) and C-reactive protein (CRP) levels in pre-vaccination plasma were unfavorable factors for overall survival (OS). Due to the safety profile and the potential clinical efficacy, the conduction of additional clinical trials of PPV for chemotherapy-resistant advanced pancreatic cancer patients is warranted.

Phase II study of personalized peptide vaccine for refractory breast cancer patients.

e13050 Background: To develop therapeutic cancer vaccine, we conducted a phase II study of personalized peptide vaccine (PPV) for refractory breast cancer patients. Methods: Thirty-four refractory breast cancer patients, including 8 triple negative (TN) cases, were enrolled to this study. A maximum of four HLA-class IA (A2, A3s, A24, A26)-matched peptides showing higher antigen-specific IgG responses were administered. Inflammatory markers, cytokines, and peptide-specific CTL and IgG responses were examined before and after vaccination to identify prognostic factors for overall survival (OS). Results: No vaccine-related severe adverse events were observed. Median numbers of preceding chemo- and/or hormone therapy regimens and median treatment duration from the recurrence to the vaccination were 2 regimens and 37 months, respectively. Three patients did not complete the 6th vaccination because of rapid disease progression. CTL or IgG boosting by PPV was observed in 16 or 18 of 31 patients at the time of 6th vaccination. IgG boosting was observed in all 24 patients tested at 12th vaccination. Median survival time of 31 patients receiving &gt; 6th vaccination after the vaccination was 474 days with 2 complete responses and 1 partial response. There were no significant differences between 8 TN cases and the other cases from points of immunological and clinical responses. Lymphocyte frequency (Hazard ratio of 0.906, p=0.019) well associated with OS by multivariate Cox proportional hazard regression analysis for pre-vaccination samples. Conclusions: Next steps of PPV for the refractory breast cancer patients were warranted because of the lower toxicity and favorite immune responses along with possible clinical benefits.

Phase I clinical study of a personalized peptide vaccination available for six different human leukocyte antigen (HLA-A2, -A3, -A11, -A24, -A31 and -A33)-positive patients with advanced cancer

The majority of peptide-based cancer vaccines under development are for human leukocyte antigen (HLA)-A2- or -A24-positive patients. To overcome this limitation, we conducted a phase I clinical study of peptide vaccines designed for cancer patients with six different HLA-A types. Eligible patients were required to have failed prior standard cancer therapies and to be positive for the HLA-A2, -A24 or -A3 (A3, A11, A31 and A33) supertype. Three sets of 8 candidate peptides (24 peptides in total) were provided for vaccination to HLA-A2(+), HLA-A24(+) and HLA-A3(+) patients, respectively. Personalization of the vaccination peptides from the candidate pool was made by considering the patients' HLA types and pre-existing levels of IgGs to the candidate peptides. Seventeen patients were enrolled in this study. The peptide vaccinations were well tolerated in all patients with no vaccine-related severe adverse events. Augmentation of cytotoxic T lymphocyte (CTL) or IgG responses specific to the vaccinated peptides was observed in 11 or 10 out of 13 cases tested, respectively. This new type of vaccine is recommended for phase II clinical trial because of its tolerability and the immune responses to the vaccinated peptides.

PHASE 1 SAFETY AND IMMUNOGENICITY TRIAL OF MALARIA VACCINE RTS,S/AS02A IN ADULTS IN A HYPERENDEMIC REGION OF WESTERN KENYA

We conducted a phase 1 trial of candidate malaria vaccine RTS,S/AS02A in western Kenya to determine its safety and immunogenicity in healthy adults in an area hyperendemic for malaria. Twenty adults were enrolled and received RTS,S/AS02A (50 microg of RTS,S in 0.5 mL of AS02A) by intramuscular injection on a 0-, 28-, and 178-day schedule. All 60 scheduled immunizations were given, and 18 of 20 volunteers completed the last study visit on day 210. The vaccine was safe and well-tolerated. There were no vaccine-related severe adverse events. The most common solicited adverse events associated with immunization were injection site pain and headache. The geometric mean concentration of antibodies to circumsporozoite protein was 1.9 microg/mL at baseline and it increased 2-4 weeks after each dose to 16, 17.8, and 36.6 microg/mL, respectively. These safety and immunogenicity data from adults in hyperendemic Kenya are comparable to data reported earlier from two trials in west African adults in hypo-endemic and meso-endemic areas of The Gambia. We conclude that in this small study, RTS,S/AS02A is safe and similarly immunogenic in malaria-exposed African adults of different ethnicity in different transmission settings.

Vaccination with the Heptavalent Pneumococcal Conjugate Vaccine Prevenar™ Provides Early Protective Antibody Responses in Children after Allogeneic Stem Cell Transplantation.

Children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at significant risk for life-threatening infections with Streptococcus pneumoniae especially in the first two years after transplantation. Due to immaturity of the immune system, immunization with conventional pneumococcal polysaccharide vaccine fails to elicit protective immunity in the majority of pediatric HSCT recipients. The heptavalent pneumococcal conjugate vaccine Prevenar™ (PCV7; Wyeth Pharma) provides effective protection from invasive disease in infants, who like aHSCT recipients are unable to respond to polysaccharide vaccines due to immunologic immaturity. Currently there is a dearth of data on the safety and efficacy of PCV7 vaccination in pediatric transplant recipients. Here we report tolerability and profound immunogenicity of PCV7 in children after HSCT and show for the first time that PCV7 provides early protective anti-pneumococcal antibody responses in a homogeneously treated cohort of pediatric HSCT recipients recruited into a prospective, multicenter vaccination trial. 53 children (median age 8,3 (1,416,9) years), who underwent HSCT from related (n=24) or unrelated (n=29) donors were immunized with three doses of PCV7 in monthly intervals starting at 6–9 months after HSCT. PCV7 was administered in combination with a hexavalent vaccine against Tetanus, Diphtheria, Pertussis, Poliovirus, Haemophilus influenzae type B and Hepatitis B (Infanrix hexa™; GlaxoSmithKline Pharma). Serum was obtained at baseline and 4–6 weeks after the 2nd and 3rd vaccine and local and systemic adverse events were recorded for 28 days after each vaccination. Responses, defined as seroconversion to protective serotype-specific antibody concentrations (Ab conc.) of 0,5 mg/ml or >2-fold increase were detected in 41.9% – 86.0% of patients (pts) after the 2nd vaccine and in 58.1% – 90.7% of pts after the 3rd vaccine (n=43). As a result of a highly significant increase in mean geometric Ab conc. (GMCs) (p<0.001) protection to all 7 vaccine serotypes was achieved in 56% and 74% of pts after the 2nd and 3rd application of PCV7 at a median of 10 and 11 months after transplantation, respectively. Even in a small subgroup of pts suffering from chronic GvHD 5/7 pts attained protective Ab conc. to 6/7 serotypes (n=7). Local and systemic tolerability was very good and no vaccine-related severe adverse events were observed. In conclusion, our data show that vaccination with PCV7 elicits highly protective anti-pneumococcal antibody responses in pediatric HSCT recipients within the 1st year following aHSCT. Therefore, PCV7 should be included in routine revaccination programs for pediatric HSCT recipients. [Display omitted]