Intention to treat--who should use ITT? Passive immunization against disease due to Haemophilus influenzae type b: concentrations of antibody to capsular polysaccharide in high-risk children. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. Haemophilus influenzae type b immunization of children with sickle cell diseases. Efficacy and safety of seven-valent conjugate pneumococcal vaccine in American Indian children: group randomised trial Serotype-specific immunoglobulin G antibody responses to pneumococcal polysaccharide vaccine in children with sickle cell anemia: effects of continued penicillin prophylaxis. Reactions to booster pneumococcal vaccination in patients with sickle cell disease Efficacy of a pneumococcal conjugate vaccine against acute otitis media. Combined schedule of 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal vaccine in children and young adults with sickle cell disease. Prevention of pneumococcal infection in children with homozygous sickle cell disease. Immunogenicity of heptavalent pneumococcal conjugate vaccine in infants.
In the clinical research er 's perfect world every patient entered into a r and omised controlled clinical trial ( RCT ) would satisfy all entry criteria , would complete their allocated treatment as described in the protocol , and would contribute data records which were complete in all respects . In practice it is doubtful if this ideal is ever achieved , and hence strategies have been developed for the analysis of RCTs which seek to protect their inferential basis from consequent biases . Such a strategy is ' intention to treat ' ( ITT ) which is frequently advocated as the preferred approach to analysis . This is particularly so for major trials design ed to establish definitively the efficacy and safety of a new medication or medical procedure . Indeed ITT has been endorsed in regulatory guidelines in Europe and the USA ( Nordic Council on Medicines , 1989 ; Food & Drug Administration , 1988 ) . But is ITT always the preferred approach ? Can it always be satisfactorily applied ? Is it a well-defined and well understood concept ? The subject of ITT regularly arouses debate and controversy . In particular the idea that a patient who has been r and omised to treatment A , but actually receives treatment B , should be assigned to the group who received A for analysis purpose s is totally incomprehensible to some . This controversy is fuelled by the fact that there are a large number of clinical trials , particularly in the early phases of research , for which ITT would indeed be inappropriate . Further fuel is added by the different attitudes to ITT in different research environments it is a constant concern in the later phases of drug regulation , for example , whereas research workers in the Medical Research Council generally show greater flexibility , probably because they are less concerned with satisfying conservative regulatory requirements . It has even been argued that ITT encourages sloppiness ' Whatever we do , give the treatment or not , it is OK since the analysis is by ITT ! ' . ITT came to prominence in connection with long-term RCTs with mortality as their major end-point . Peto and co-workers laid out the general principles for the design and analysis of such studies in their comprehensive and highly influential publications in this journal ( Peto et al. , 1976 , 1977 ) . They did not use the term ' intention to treat ' but did advocate that ' even patients who do not get the proper treatment must not be withdrawn from the analysis ' . Their guidance is detailed : the various ways in which patients may fail to complete the study as per protocol are all discussed , together with the possibility that the patients who so fail may differ in characteristics , or numbers , from treatment arm to treatment arm . Such differences are the source of the bias which ITT attempts to avoid any analysis which omits patients is open to bias because it no longer compares the groups as r and omised . However , although Peto and coworkers do recommend that all properly r and omised patients should be included in the analysis regardless of protocol deviation , they do leave open the possibility for some inappropriately r and omised patients to be excluded , and thus stop short of espousing the inclusion of all r and omised patients From the pooled plasma of 54 adult donors immunized with Haemophilus influenzae type b capsular polysaccharide ( CP )  , a human hyperimmune globulin termed bacterial polysaccharide immune globulin ( BPIG ) was prepared . The pharmacokinetics of antibody to H. influenzae type b CP in high-risk children was compared after BPIG and conventional immune serum globulin ( ISG ) were administered intramuscularly at a dose of 0.5 - 0.6 ml/kg . The increase in antibody level four to seven days after injection was ninefold higher with BPIG than with ISG and remained higher throughout the three-month follow-up period . The mean half-life of antibody to H. influenzae type b CP was similar after BPIG ( 27 days ) and ISG ( 29 days ) . Antibody levels returned to baseline one to two months after ISG but remained significantly above baseline three months after BPIG ( mean concentration , 385 ng/ml ) . Based on the assumption that 150 ng of IgG antibody to H. influenzae type b CP/ml is the minimal protective level , it is concluded that a single intramuscular dose of 0.5 ml of BPIG/kg will protect children for four months BACKGROUND Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children . We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a r and omized , double-blind study in Soweto , South Africa . METHODS At 6 , 10 , and 14 weeks of age , 19,922 children received the  9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin ( CRM197 ) , and 19,914 received placebo .  All children received Haemophilus influenzae type b conjugate vaccine .  Efficacy and safety were analyzed according to the intention-to-treat principle . RESULTS Among children without human immunodeficiency virus ( HIV ) infection , the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent ( 95 percent confidence interval , 39 to 97 ; 17 cases among controls and 3 among vaccine recipients ) . Among HIV-infected children , the efficacy was 65 percent ( 95 percent confidence interval , 24 to 86 ; 26 and 9 cases , respectively ) . Among children without HIV infection , the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent ( 95 percent confidence interval , 2 to 35 ; 212 cases in the control group and 169 in the vaccinated group ) in the intention-to-treat analysis and by 25 percent ( 95 percent confidence interval , 4 to 41 ; 158 and 119 cases , respectively ) in the per- protocol analysis ( i.e. , among fully vaccinated children ) . The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent ( 95 percent confidence interval , 19 to 88 ; 21 cases in the control group and 7 in the vaccinated group ) , and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent ( 95 percent confidence interval , 16 to 78 ; 32 and 14 cases , respectively ) . CONCLUSIONS Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia . The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection Haemophilus influenzae type B vaccine is recommended for children 1.5 to 6 years of age with sickle cell anemia , but the adequacy of their response is unknown . A total of 69 children with sickle cell syndromes , 1.5 to 5.6 years of age , were immunized with two vaccines alternatively , single blind . PRP vaccine was given to 36 children and a diphtheria toxoid conjugated vaccine , PRP-D , was given to 36 . Coded pre- and postvaccine sera were tested by radioimmunoassay for anti-PRP antibody . The groups did not differ in age distribution or type of sickle hemoglobinopathy .  Preexisting antibody levels were low in both vaccine groups ; 65 % were less than 0.15 microgram/mL. The vaccines were safe but associated with frequent minor reactions .  PRP-D gave higher geometric mean titers and mean fold titer increase than PRP in all children ( 15.58 micrograms/mL [ 234-fold ] v 2.63 micrograms/mL [ 29-fold ] ) and in the subgroups 1.5 to 2.5 years of age or with pretiter values less than 0.15 microgram/mL. Titers for 64 % of children receiving PRP and 94 % receiving PRP-D were greater than or equal to 1.0 microgram/mL. Thus , both vaccines were useful in this population , but PRP-D was more immunogenic . Duration of antibody levels postvaccination , booster responses , and PRP-D immunogenicity in younger children with sickle cell syndromes all require further study BACKGROUND Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years . Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world . We aim ed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine ( PnCRM7 ) against such disease . METHODS In a group-r and omised study , we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations ; meningococcal type C conjugate vaccine ( MnCC ) served as the control vaccine . Vaccine schedules were determined by age at enrollment . We recorded episodes of invasive pneumococcal disease and serotyped isolates . Analyses were by intention to treat and per protocol . FINDINGS 8292 children enrolled in the trial . In the per protocol analysis of the primary efficacy group ( children enrolled by 7 months of age ) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group ; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group . After group r and omisation had been controlled for , the per protocol primary efficacy of PnCRM7 was 76.8 % ( 95 % CI -9.4 % to 95.1 % ) and the intention-to-treat total primary efficacy was 82.6 % ( 21.4 % to 96.1 % ) . INTERPRETATION PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population . Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule OBJECTIVES ( 1 ) To determine serotype-specific IgG antibody responses to reimmunization with pneumococcal polysaccharide vaccine at age 5 years in children with sickle cell anemia and ( 2 ) to determine whether continued penicillin prophylaxis had any adverse effects on these responses . STUDY DESIGN Children with sickle cell anemia , who had been treated with prophylactic penicillin for at least 2 years before their fifth birthday , were r and omly selected at age 5 years to continue penicillin prophylaxis or to receive placebo treatment .  These children had been immunized once or twice in early childhood with pneumococcal polysaccharide vaccine and were reimmunized at the time of r and omization . RESULTS Serotype-specific IgG antibody responses to reimmunization varied according to pneumococcal serotype but in general were mediocre or poor ; the poorest response was to serotype 6B . The antibody responses were similar in subjects with continued penicillin prophylaxis or placebo treatment , and in subjects who received one or two pneumococcal vaccinations before reimmunization . The occurrence of pneumococcal bacteremia was associated with low IgG antibody concentrations to the infecting serotype . CONCLUSIONS Reimmunization of children with sickle cell anemia who received pneumococcal polysaccharide vaccine at age 5 years induces limited production of serotype-specific IgG antibodies , regardless of previous pneumococcal vaccine history . Continued penicillin prophylaxis does not interfere with serotype-specific IgG antibody responses to reimmunization Repeat ( booster ) pneumococcal vaccination was administered to 32 patients with sickle cell disease in a double blind , placebo-controlled crossover study as early as 2.3 years after initial immunization . A significantly greater proportion of patients reported local pain , swelling or redness after booster , as compared to that after placebo ( P < 0.001 ) , and pneumococcal antibody titer before vaccination was the predominant predictive variable for the development of fever , local pain and swelling after booster . A comparison of reaction rates following primary or booster immunization showed no significant differences in the frequency of reported symptoms except for muscle pain which occurred less frequently after booster ( P < 0.005 ) . The concern for adverse reactions after repeat pneumococcal vaccination should not be an obstacle to the pursuit of further studies on the efficacy of pneumococcal vaccine and booster responses BACKGROUND Ear infections are a common cause of illness during the first two years of life . New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae . METHODS We enrolled 1662 infants in a r and omized , double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197 . The children received either the study vaccine or a hepatitis B vaccine as a control at 2 , 4 , 6 , and 12 months of age . The clinical diagnosis of acute otitis media was based on predefined criteria , and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy . RESULTS Of the children who were enrolled , 95.1 percent completed the trial . With the pneumococcal vaccine , there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria-tetanus-pertussis and Haemophilus influenzae type b vaccine that was administered simultaneously . There were 2596 episodes of acute otitis media during the follow-up period between 6.5 and 24 months of age . The vaccine reduced the number of episodes of acute otitis media from any cause by 6 percent ( 95 percent confidence interval , -4 to 16 percent [ the negative number indicates a possible increase in the number of episodes ] ) , culture-confirmed pneumococcal episodes by 34 percent ( 95 percent confidence interval , 21 to 45 percent ) , and the number of episodes due to the serotypes contained in the vaccine by 57 percent ( 95 percent confidence interval , 44 to 67 percent ) . The number of episodes attributed to serotypes that are cross-reactive with those in the vaccine was reduced by 51 percent , whereas the number of episodes due to all other serotypes increased by 33 percent . CONCLUSIONS The heptavalent pneumococcal polysaccharide-CRM197 conjugate vaccine is safe and efficacious in the prevention of acute otitis media caused by the serotypes included in the vaccine We compared the immunogenicity of 7-valent pneumococcal-conjugate vaccine plus 23-valent pneumococcal vaccine to immunization with 23-valent vaccine only in individuals > or = 2 years of age with sickle cell disease .  IgG pneumococcal antibody concentrations were higher in the combined schedule group with no increase in side effects observed after immunization with 23-valent vaccine The efficacy of prophylactic penicillin and of 14 valent pneumococcal vaccine in preventing pneumococcal infection in homozygous sickle cell ( SS ) disease was investigated in 242 children aged 6 months to 3 years at entry . In the first five years of the trial there were 11 pneumococcal infections in the pneumococcal vaccine treated group , 10 by serotypes present in the vaccine . Type 23 accounted for five of these , and there was evidence of higher infection rates in those given the vaccine before age 1 . No pneumococcal isolations occurred in the penicillin group while receiving penicillin , although four isolations occurred within one year of stopping penicillin . Probably the most effective prophylaxis against pneumococcal infection requires penicillin beyond the age of 3 . The age at which pneumococcal vaccine should be given must await further data on antibody response and clinical efficacy in these patients OBJECTIVE To evaluate the safety , immunogenicity , and immunologic memory in young infants of a seven-valent ( 6B , 14 , 19F , 23F , 18C , 4 , 9V ) pneumococcal vaccine conjugated to the outer membrane protein complex of Neisseria meningitidis . VACCINEES : Healthy 2-month-old infants 12- to 15-month-old control infants were recruited from participating private practice s. METHODS Infants ( n = 25 ) were vaccinated at 2 , 4 , and 6 months of age with the conjugated pneumococcal vaccine , followed by a single dose of licensed pneumococcal polysaccharide vaccine ( n = 20 ) at 12 to 15 months of age . Thirteen infants who had not received the investigational pneumococcal conjugate vaccine  served as control subjects and were given a single dose of the licensed pneumococcal polysaccharide vaccine at 12 to 15 months of age . RESULTS The investigational pneumococcal conjugate vaccine was well tolerated by infants . The vaccine was highly immunogenic in young infants , with significant increases in antibody to all seven serotypes after either two or three injections . At 12 to 15 months of age , infants who had been primed with the investigational pneumococcal conjugate vaccine had a brisk immunologic response to the booster injection of the licensed pneumococcal polysaccharide vaccine . Control infants , who received a single primary injection of the licensed pneumococcal polysaccharide vaccine , had negligible immunologic responses to four of the seven serotypes and low responses to the other three types . CONCLUSION The investigational seven-valent pneumococcal conjugate vaccine administered to young infants was well tolerated and highly immunogenic and provided immunologic memory to an injection of the licensed pneumococcal polysaccharide vaccine
BACKGROUND People with sickle cell disease are particularly susceptible to pneumococcal infection , which may be fatal .
Infants ( children aged up to 23 months ) are at particularly high risk , but conventional polysaccharide pneumococcal vaccines may be ineffective in this age group .
New conjugate pneumococcal vaccines are now available , which may help to reduce the incidence of infection in people with sickle cell disease .
OBJECTIVES To determine the efficacy of pneumococcal vaccines for reducing morbidity and mortality in people with sickle cell disease .
REVIEW ER 'S CONCLUSIONS Previous trials have shown that conjugate pneumococcal vaccines are safe and effective in normal healthy patients , even those under the age of two years .