Stanley A. Gall

Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING GlaxoSmithKline Biologicals (Belgium).

Influence of compression rate on initial success of resuscitation and 24 hour survival after prolonged manual cardiopulmonary resuscitation in dogs.

The influence of chest compression rate on initial resuscitation success and 24 hr survival after prolonged manual cardiopulmonary resuscitation (CPR) was investigated in 26 morphine-anesthetized dogs (17 to 30 kg). After placement of aortic and right atrial micromanometers and induction of ventricular fibrillation, manual CPR was commenced immediately and continued for 30 min. One group of 13 dogs underwent manual CPR at a compression rate of 60/min, and the other group at a rate of 120/min. The compression durations in the two groups were not significantly different (51.7 +/- 1.8% at 60/min vs 51.6 +/- 1.9% at 120/min). No drugs other than sodium bicarbonate were administered during CPR. A maximum of three attempts was permitted to defibrillate the heart. Successfully defibrillated animals were followed for 24 hr, during which time no treatment, other than naloxone, was given to reverse the effects of morphine. Arterial blood pH, PCO2, and PO2 were not significantly different in the two groups throughout the CPR period. When compared with the compression rate of 60/min, the compression rate of 120/min produced more successfully defibrillated animals (12/13 at 120/min vs 2/13 at 60/min, p less than .002) and more 24 hr survivors (8/13 at 120/min vs 2/13 at 60/min, p less than .03). All 24 hr survivors were conscious and able to sit, stand, and drink normally. One 24 hr survivor in each group had difficulty walking. Improved survival with the high-rate compression technique was consistent with the significantly higher mean aortic (systolic and diastolic) and coronary perfusion pressures attained with high-rate compressions (all p less than .002). Although the clinical applicability of these findings has yet to be demonstrated, they provide empirical support for the recent decision to increase the chest compression rate for manual CPR recommended by the American Heart Association, and indicate that the hemodynamic and survival benefits of faster compression rates in this experimental preparation were not dependent on covariant alterations in compression duration.

Maternal immunization with tetanus–diphtheria–pertussis vaccine: effect on maternal and neonatal serum antibody levels

OBJECTIVE We sought to determine whether tetanus-diphtheria-pertussis vaccination (Tdap) in pregnancy provides newborns antibodies against pertussis when compared to mothers who did not receive Tdap. STUDY DESIGN Paired maternal and umbilical cord blood samples were collected at the time of delivery and the serum stored at -86°C. For each paired sample of maternal and cord blood, the medical chart and vaccine history was reviewed to determine whether Tdap was received or not. RESULTS Newborns born from mothers who received Tdap during pregnancy had significantly higher concentrations of diphtheria antitoxin (P < .001), tetanus antitoxin (P = .004), and antibodies to pertussis toxin (P < .001), filamentous hemagglutinin (P = .002), pertactin (P < .001), and fimbriae 2/3 (P < .001) when compared to newborns from mothers who did not receive Tdap. There was a significant increase in the odds that newborns from mothers who received Tdap during pregnancy have antibodies that may provide protection against diphtheria (P = .0141), pertussis toxin (P < .0001), and fimbriae 2/3 (P = .0146). CONCLUSION Administering Tdap during pregnancy increases antibody titers against diphtheria and pertussis antigens. Maternal Tdap may prevent neonatal pertussis infection.

Intra-amniotic bacterial colonization in premature labor

Bacterial culturing was performed on amniotic fluid obtained by transabdominal amniocentesis from 33 patients with singleton pregnancies who were in idiopathic premature labor with intact membranes prior to the thirty-fifth week of gestation. Bacteria were isolated in seven patients (21.2%). The patients who were at highest risk for intra-amniotic colonization were those who had two or more clinical parameters suspicious for intra-amniotic infection in a pregnancy prior to the thirtieth week. Anaerobic bacteria were isolated from all seven patients. Only one patient had mixed aerotolerance isolates. Anaerobic that were classified as significant pathogens were isolated in four patients. Three patients had isolates that grew on primary plates, and the rest were recovered only from broth. The greatest impact of intra-amniotic bacterial colonization in premature labor with intact membranes on perinatal outcome is expressed in extreme prematurity and appears to be a function of the pathogenicity and concentration of the offending organism(s).

Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 vaccine: a combined analysis of five randomized controlled trials.

OBJECTIVE: To present a combined analysis of the pregnancy outcomes for women aged up to 45 years enrolled in five phase III clinical studies of the prophylactic quadrivalent human papillomavirus 6/11/16/18 vaccine. METHODS: Twenty thousand five hundred fifty-one women aged 15–45 years received quadrivalent HPV vaccine or placebo at day 1 and months 2 and 6. Urine pregnancy tests were performed immediately before each injection; participants testing positive were not vaccinated. Women who became pregnant after enrollment were discontinued from further vaccination until resolution of pregnancy. All pregnancies were followed for outcomes. RESULTS: During the studies, 1,796 vaccine and 1,824 placebo recipients became pregnant, resulting in 2,008 and 2,029 pregnancies with known outcomes. No significant differences were noted overall for the proportions of pregnancies resulting in live birth, fetal loss, or spontaneous abortion. A total of 40 neonates born to vaccinated women and 30 neonates born to women given placebo had one or more congenital anomalies (P=.20). The anomalies were diverse and consistent with those most commonly observed in the general population. The vaccine was well tolerated among women who became pregnant. CONCLUSION: Administration of quadrivalent human papillomavirus vaccine to women who became pregnant during the phase III clinical trials did not appear to negatively affect pregnancy outcomes. The vaccine is a U.S. Food and Drug Administration pregnancy category B medication (animal studies revealed no evidence of fetal harm, but there are no adequate and well-controlled studies in pregnant women); however, vaccination is not recommended during pregnancy. Postlicensure surveillance is ongoing. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00092521, NCT00092534, NCT00092495, NCT00092547 and NCT00090220. LEVEL OF EVIDENCE: II

Sequence of mitral valve motion and transmitral blood flow during manual cardiopulmonary resuscitation in dogs.

According to the thoracic pump model of cardiopulmonary resuscitation (CPR), the heart serves as a passive conduit for blood flow from the pulmonary to the systemic vasculature, necessitating an open mitral valve and anterograde transmitral blood flow during chest compression. To assess the applicability of this model to manual CPR techniques, two-dimensional echocardiograms were recorded from the right chest wall and/or the esophagus in nine dogs (18 to 26 kg) during manual CPR. The aortic valve opened with chest compression and closed with release, while the pulmonary and tricuspid valve leaflets closed with compression and opened during release. The mitral valve remained open during ventilation alone and during abdominal compressions. With the onset of brief, high-velocity (high-impulse) chest compressions, the mitral valve closed rapidly and the left ventricle was deformed, whether compressions were applied to the sternum or the left mid-chest wall. The mitral valve reopened with release of each compression. Left atrial echocardiographic contrast injections confirmed the absence of anterograde transmitral blood flow during high-impulse compression and its presence during release. Failure of mitral leaflet approximation during chest compression was observed only when a very low-velocity, prolonged (low-impulse) compression technique was used, or when regions that did not directly overlie the heart were compressed. Consistent with these observations, simultaneous recordings of the left ventricular and left atrial pressures during high-impulse sternal compressions in five dogs (19 to 25 kg) demonstrated peak and mean left ventriculoatrial pressure gradients of 38.5 +/- 4.0 and 13.5 +/- 2.9 mm Hg, respectively, and these pressure gradients declined with less impulsive compressions. The observations made during all but low-impulse chest compressions are inconsistent with the thoracic pump model, and support direct cardiac compression as the primary mechanism of forward blood flow with more impulsive manual chest compression techniques.

Ellipsoidal shell subtraction model of right ventricular volume. Comparison with regional free wall dimensions as indexes of right ventricular function.

Pulse-transit sonomicrometry was used to measure the base-apex (a), anteroposterior (b), and septal-free wall (c) diameters of the left ventricle and the septal-free wall diameter of the right ventricle (d) in eight excised and three isolated, pump-perfused canine heart preparations, as well as in nine conscious dogs. In the three perfused hearts and in four of the excised hearts, right ventricular free wall regional segment lengths and segment area also were assessed. Biventricular volumes were measured directly with intracavitary balloons in all isolated hearts. When left ventricular balloon volume was held constant, relations between right ventricular free wall dimensions and right ventricular balloon volume were highly linear. With increments in left ventricular volume, however, these relations remained linear but shifted progressively upward, indicating an independent relation between right ventricular free wall dimensions and left ventricular cavitary volume. An ellipsoidal shell subtraction model (pi/6.abd minus right ventricular free wall volume) was developed to estimate right ventricular cavitary volume from cardiac dimensions. With this method, a highly linear relation was observed between calculated right ventricular volume and right ventricular balloon volume (mean r = 0.99 +/- 0.01). Moreover, this relation appeared to be independent of changes in left ventricular balloon volume. With the shell subtraction model, dynamic right ventricular volume was computed in nine conscious dogs, and in four, stroke volume derived from dimensions was compared with right ventricular stroke volume measured with ultrasonic flow probes. A highly linear relation was observed, suggesting the accuracy of the shell subtraction method in vivo. Right ventricular end-systolic pressure-volume and stroke work/end-diastolic volume relations then were evaluated, and both proved to be highly linear in the right ventricle (both mean r = 0.99 +/- 0.01). Thus, the shell subtraction model allows a simple estimate of dynamic right ventricular volume in the intact heart and facilitates assessment of right ventricular performance in vivo.

Interferon for the therapy of condyloma acuminatum

Lymphoblastoid interferon, Wellferon, was used to treat patients with resistant and persistent condyloma acuminatum at initial doses of 5, 3, and 1 million unit/square meter (Mu/M2). The objectives of this study were to evaluate the efficacy and toxicity of, and tolerance to, intramuscular and intralesional interferon. Seventeen patients were treated with 5 Mu/M2, 14 patients with 1 Mu/M2, and 37 patients with 3 Mu/M2; daily administration was followed by three-times-a-week dosing. The complete response rate in patients receiving initial dose of interferon of 5 Mu/M2 was 69%, that for doses of 1 Mu/M2 was 43%, and that for doses of 3 Mu/M2 was 57%. All patients given interferon developed initial elevations of temperature of limited duration, whereas all patients given the 5 Mu/M2 dose had to have the amount reduced because of biologic side effects. However, only five of 37 (14%) of the patients given 3 Mu/M2 required a reduction in the dosage, and no patient given 1 Mu/M2 needed to have the dosage reduced. These studies suggest that interferon is efficacious in the treatment of resistant and persistent condyloma acuminatum, and that the biologic side effects were dose-related, well tolerated, and not life-threatening.

Efficacy of human lymphoblastoid interferon in the therapy of resistant condyloma acuminata

The efficacy and tolerance of human lymphoblastoid interferon (Wellferon) were studied in an open label trial of 17 patients with resistant and persistent condyloma acuminata. Patients were treated intramuscularly with 5 X 10(6) U (5 MU)/m2 daily for 28 days followed by thrice weekly injections for two weeks. Sixteen patients were considered evaluable; eight experienced complete clearance, seven had significant reduction (greater than 50%) in lesion size, and one showed no response during the course of this trial. Biologic side effects of interferon occurred in all patients during initial dosing and diminished during thrice weekly therapy. Intramuscular injections and associated side effects were tolerated well. This study shows that systemic human lymphoblastoid interferon is active in treating severe recurrent genital warts in women with a history of recalcitrant disease.

Preinduction cervical ripening with prostaglandin E2 (Prepidil) gel.

The effect of preinduction cervical ripening with Prepidil, a commercially prepared prostaglandin E2 gel (0.5 mg), on the outcome of induction of labor with intravenous oxytocin was investigated. Fifty-nine pregnant women were randomized either to receive intracervical application of the gel or to undergo sham application. Compared to control subjects, patients in the group given Prepidil had significant increases in cervical Bishop scores, shorter induction-to-delivery intervals, lower maximum doses of oxytocin, and fewer days of induction. Systemic side effects were minimal, but 37% (11 of 30) of the gel-treated patients experienced labor prior to receiving oxytocin and 20% (six of 30) were actually delivered during the 12-hour ripening period. No differences in route of delivery or fetal outcome were found between the two groups.