John 1984.

Study characteristics
Methods	RCT. Participants randomised to 4 treatment groups: penicillin prophylaxis with the addition of either 14‐valent pneumococcal vaccine (Group 1) or Hinfuenzae B vaccine (Group 3) or either of the preceding vaccines without penicillin prophylaxis( 14‐valent vaccine only group 2 and H influenzae B vaccine only Group 4).
Participants	The trial was conducted at the sickle cell clinics of the University Hospital of the West Indies, Kingston, Jamaica. Children between 6 months and 3 years of age and with homozygous SCD were eligible, 265 children were randomised, of which 23 of subsequently withdrawn, mainly because of a revision of their genotype, leaving a total of 242 children as trial participants. A protocol revision was made as penicillin was withheld in 16 children because of remote addresses and insufficient time after enrolment and randomisation to assess the efficacy of IM penicillin treatment. These children were assigned to respective vaccine only groups. Trial duration: 5 years.
Interventions	Penicillin monthly IM injection; pneumococcal 14 valent vaccine containing the following Danish types of purified pneumococcal polysaccharide antigens: 1, 2, 3, 4, 6A, 7F, 8, 9N, 12F, 14, 18C, 19F, 23F, and 25. H influenzae type B vaccine.
Outcomes	Incidence of pneumococcal infection (isolated). A 2x2 factorial design was used to compare (a) the response to pneumococcal vaccine with that to Hinfluenzae type B vaccine as a capsular polysaccharide antigen control and (b) the effect of penicillin with that of no penicillin.
Notes	No documented declarations of interests among the primary researchers.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"A total of 265 children were randomised to the four study groups." No details were given of the method of randomization we are therefore unable to fully assess the risk of selection bias.
Allocation concealment (selection bias)	High risk	"A revision of protocol withholding penicillin was necessary for 16 patients, eight of whom lived at remote addresses and eight of whom entered between 31 and 35 months of age, which would have resulted in too short a treatment period to assess efficacy. These 16 were assigned to the corresponding vaccine groups without penicillin."
Blinding (performance bias and detection bias) All outcomes	Low risk	Trial not blinded; however, the primary trial outcome (number of participants developing S pneumoniae infection confirmed with cultures or number of deaths as a result of such an infection) and the secondary study outcome (adverse drug reaction) are not affected by the fact that blinding did not take place.
Incomplete outcome data (attrition bias) All outcomes	High risk	A total of 265 children were randomised to the four study groups, but 23 of these were subsequently withdrawn, mostly due to revision of genotype. "The trial was terminated prematurely in 25 children owing to splenectomy in 20, emigration in four, and the clinical decision to use prophylactic penicillin in one child with recurrent pneumococcal meningitis In these cases results up to the time of leaving the study were included in the analysis. There were seven deviations from the protocol caused by refusal to take penicillin after two and four injections (two), death before institution of randomised treatment (one), failure to treat with penicillin because of an error in age (one), inadvertent administration of penicillin to patients joining the study between 31 and 35 months of age (two), and removal to an inaccessible address, so that penicillin had to be stopped (one)." Additionally, the study groups were also uneven with more participants in the penicillin group (143 in the penicillin group compared to 90 in the control group) and an "Intention to treat analysis was also undertaken" after participants were reassigned to protocol groups.
Selective Reporting (Reporting Bias)	Low risk	"The pneumococcal prevention study began in May 1978. A 2x2 factorial design was used to compare (a) the response to pneumococcal vaccine with that to Haemophilus influenzae type B vaccine as a capsular polysaccharide antigen control and (b) the effect of penicillin with that of no penicillin." All outcomes were satisfactorily reported.
Other potential Sources of Bias	Low risk	None known.