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SUPPLEMENTARY APPENDIX A

SUPPLEMENTARY METHODS

1. Search strings used for PubMed [1]

The following limits were used for all the strings described below:

AND (Brazil*[tw] OR Brasil*[tw])

AND ("2011/01/01"[Date - Publication] : "2015/04/30"[Date - Publication])

AND ("english"[Language] OR "portuguese"[Language] OR "spanish"[Language])

In addition, this search was updated twice up to November 2015 and February 2016 using the

following limits:



Topic String

Vaccines "Pneumococcal Vaccines"[Mesh] OR pneumococcal conjugate vaccin*[tw]

OR 10-valent[all] OR PHiD-CV[all] OR PCV10[all] OR PCV-10[all] OR

Synflorix[all] OR ten-valent[all] OR pneumococcal non-typeable

Haemophilus influenzae protein D conjugate vaccine

Otitis (“Otitis media”[Mesh] OR otitis[tw] OR acute otitis media[tw] OR AOM[tw]

OR OM[tw] OR OME[tw] OR tympanostomy[tw] OR myringotomy[tw] OR

otorrhea[tw] OR chronic suppurative otitis media [tw] OR CSOM[tw]) AND

(epidemiology[tw] OR prevalence[tw] OR incidence[tw])

Pneumonia ("Pneumonia"[Mesh] OR “Community-Acquired Infections”[Mesh] OR

CAP[tw] OR lower respiratory tract infection*[tw] OR respiratory

infection[tw])

AND (epidemiology[tw] OR prevalence[tw] OR incidence[tw])

Invasive

disease

(“Invasive Pneumococcal Disease“[tw] OR IPD[tw] OR invasive bacterial

disease[tw] OR “Bacteremia”[Mesh] OR bacteremi*[tw] OR bacteraemi*[tw]

OR “Meningitis”[Mesh] OR sepsis[tw] or empyema[tw] OR septicemia[tw]

OR septicaemia[tw])


AND (Respiratory bacterial pathogen*[tw] OR "Streptococcus

pneumoniae"[Mesh] OR streptococcus pneumonia*[tw] OR S.

pneumonia*[tw] OR pneumococcal[tw] OR pneumococ*[tw] OR

"Haemophilus influenzae"[Mesh] OR haemophilus influenza*[tw] OR

NTHi[tw] OR Hib[tw] OR hemophilus[tw] OR haemophilus[tw])

Carriage ("Carrier State"[Mesh] OR carriage[tw] OR "Nose/microbiology"[Mesh] OR

"pharynx/microbiology"[Mesh] OR "Nasopharynx/microbiology"[Mesh] OR

"Oropharynx/microbiology"[Mesh] OR colonization[tiab] OR

colonisation[tiab] OR colonizing[tiab] OR colonising[tiab] OR bacterial

load[tiab] OR bacterial density[tiab])







Herd

protection

("Immunity, Herd”[Mesh] OR herd protection[tw] OR herd immunity[tw] OR

indirect protection[tw] OR indirect immunity[tw] OR herd effect[tw])






Other

related

diseases or

health

problems

(bronchitis[tw] OR bronchiolitis[tw] OR asthma[tw] OR reactive airway

disease[tw] OR sinusitis[tw] OR pharyngitis[tw] OR tonsillitis[tw] OR

conjunctivitis[tw])


AND (child*[tw] OR pediatric*[tw] OR paediatric*[tw])

2. Search strings used for Embase [2]

The search was performed on May 5th, 2015.

The following limits were used for all the strings described below:

AND 'brazil'/exp OR brazil OR brasil

AND [2011-2015]/py

AND ([english]/lim OR [portuguese]/lim OR [spanish]/lim)

Topic String

Vaccines 'synflorix'/exp OR 'pneumococcal conjugate vaccine'/exp OR pcv10 OR 'pcv

10' OR '10 valent'

Otitis 'otitis'/exp AND media OR aom OR tympanostomy OR 'myringotomy'/exp

OR 'otorrhea'/exp OR (chronic AND suppurative)

AND ('epidemiology'/exp OR 'prevalence'/exp OR 'incidence'/exp)

Pneumonia 'pneumonia' AND 'community acquired' OR (lower AND respiratory AND

tract AND near AND infection) OR (respiratory AND infection)


Invasive

disease

'invasive and pneumococcal and disease' OR ipd OR (invasive AND disease)

OR 'bacteremia'/exp OR 'meningitis'/exp OR 'sepsis'/exp OR 'septicemia'/exp

AND 'epidemiology'/exp OR 'prevalence'/exp OR 'incidence'/exp

AND 'streptococcus'/exp AND pneumoniae OR pneumococcal OR

pneumococcus OR 'haemophilus'/exp AND influenzae OR nthi OR hib OR

(respiratory AND bacterial AND pathogen)

Carriage carrier OR carriage OR 'nose'/exp OR 'pharynx'/exp OR 'nasopharynx'/exp

OR 'oropharynx'/exp AND 'microbiology'/exp OR colonization OR

colonisation OR colonizing OR colonising OR (bacterial AND load) OR

(bacterial AND 'density'/exp)




Herd

protection

'herd immunity'/exp OR 'herd protection' OR 'herd effect' OR 'indirect

protection' OR 'indirect immunity' OR 'indirect effect'




Other

related

diseases or

health

problems

'bronchitis'/exp OR 'bronchiolitis'/exp OR 'asthma'/exp OR (reactive AND

airway AND disease) OR 'sinusitis'/exp OR 'pharyngitis'/exp OR

'tonsillitis'/exp OR 'conjunctivitis'/exp


AND ('child'/exp OR pediatric OR paediatric)

3. Search strings used for SciELO [3]

The search was performed on May 5th, 2015.

Topic String

Vaccines Pneumococcal Vaccines OR pneumococcal conjugate vaccine OR 10-valent

OR PHiD-CV OR PCV10 OR PCV-10 OR Synflorix OR ten-valent OR

pneumococcal non-typeable Haemophilus influenzae protein D conjugate

vaccine [All indexes]

AND 2011 OR 2012 OR 2013 OR 2014 OR 2015 [Publication year]

Otitis (Otitis media OR otitis OR acute otitis media OR AOM OR OM OR OME

OR tympanostomy OR myringotomy OR otorrhea OR chronic suppurative

otitis media OR CSOM)

AND (epidemiology OR prevalence OR incidence) [All indexes]


Pneumonia (Pneumonia OR Community-Acquired Infections OR CAP OR lower

respiratory tract infection OR respiratory infection)

AND (epidemiology OR prevalence OR incidence) [All indexes]


Invasive

disease

(Invasive Pneumococcal Disease OR IPD OR invasive bacterial disease OR

Bacteremia OR bacteremia OR bacteraemia OR Meningitis OR sepsis or

empyema OR septicemia OR septicaemia) AND (Respiratory bacterial

pathogen OR "Streptococcus pneumoniae" OR streptococcus pneumonia OR

S. pneumonia OR pneumococcal OR "Haemophilus influenzae" OR

haemophilus influenza OR NTHi OR Hib OR hemophilus OR haemophilus

OR pneumococ) AND (epidemiology OR prevalence OR incidence) [All

indexes]


Carriage (Carrier State OR carriage OR Nose microbiology OR pharynx microbiology

OR Nasopharynx microbiology OR Oropharynx microbiology OR

colonization OR colonisation OR colonizing OR colonising OR bacterial load

OR bacterial density)

AND (Respiratory bacterial pathogen OR "Streptococcus pneumoniae" OR

streptococcus pneumonia OR S. pneumonia OR pneumococcal OR

"Haemophilus influenzae" OR haemophilus influenza OR NTHi OR Hib OR

hemophilus OR haemophilus OR pneumococ) AND (epidemiology OR

prevalence OR incidence) [All indexes]


Herd

protection

(herd protection OR herd immunity OR indirect protection OR indirect

immunity OR herd effect)

AND (Respiratory bacterial pathogen OR "Streptococcus pneumoniae" OR

streptococcus pneumonia OR S. pneumonia OR pneumococcal OR

"Haemophilus influenzae" OR haemophilus influenza OR NTHi OR Hib OR

hemophilus OR haemophilus OR pneumococ) [All indexes]


Other

related

diseases or

health

problems

(bronchitis OR bronchiolitis OR asthma OR reactive airway disease OR

sinusitis OR pharyngitis OR tonsillitis OR conjunctivitis) AND

(epidemiology OR prevalence OR incidence) AND (child OR children OR

pediatric OR paediatric) [All indexes]


4. Search strategy for congress abstracts

We searched for additional data in the available abstracts of relevant scientific congresses

held between 2011 and 2015: International Symposium on Pneumococci and

Pneumococcal Diseases (ISPPD), 2012, 2014; Congreso Latinoamericano de Infectología

Pediátrica (SLIPE), 2013; Interscience Conference of Antimicrobial Agents and

Chemotherapy (ICAAC), 2011–2014; Annual Meeting of the European Society for

Paediatric Infectious Diseases (ESPID), 2015; World Congress of the World Society for

Pediatric Infectious Diseases (WSPID), 2011; International Congress on Infectious

Diseases (ICID), 2014; IDWeek, 2012–2014; Congresso Brasileiro de Pediatria, 2013;

Congresso Brasileiro de Pneumologia Pediátrica, 2014; and Congresso Brasileiro de

Infectologia Pediátrica, 2014. Searches were done using “Brazil” as a key word, except

for the three Brazilian congresses, for which “pneumonia”, “otitis”, “invasive”, “vacina

pneumococica”, or “meningitis” were used. Abstracts were screened using the same

inclusion and exclusion criteria as for the publications. Abstracts were not included if the

results were also described in a published article included in the analysis. When several

abstracts were presented for the same study, only the most recent or complete results were

used.

5. Inclusion and exclusion criteria for the analysis

Reports eligible for inclusion in this analysis have to meet the following criteria:

Reports have to be in English, Portuguese, or Spanish and published between January

2011 and April 2015. An update of the search was conducted in PubMed only to

identify reports published between May and November 2015.

Randomized controlled trials (RCTs), non-randomized studies, or observational

studies (case-control studies or pre-/post-vaccine introduction time series) that

assessed the effects of the introduction of PHiD-CV in Brazil on invasive disease,

pneumonia, otitis media, nasopharyngeal carriage, serotype distribution, or heard

protection in all age groups. The year 2010 was considered as a transition period.

Reports that evaluated epidemiological parameters (e.g., prevalence or incidence) for

diseases related to the same topics, before and after 2010 in children ≤ 5 years of age

(bronchitis, bronchiolitis, asthma, reactive airway disease, sinusitis, pharyngitis,

tonsillitis, and conjunctivitis).

Reports eligible for this study must not meet any of the following criteria:

Reports of animal studies; in vitro studies; models; vaccine immunogenicity or safety

studies; cost-effectiveness or health economics studies; public health programs or

recommendations; case reports; reviews, editorials or comments; studies evaluating

treatments such as antibiotics; studies of virus etiology only; studies conducted among

populations with chronic diseases not representative of the general population; time-

series analysis conducted only before or after PHiD-CV introduction; or studies whose

analysis period was unspecified.

6. Data extraction and analysis

An EndNote™ (Thomson Reuters) database containing all the included and excluded reports

was created. Extracted data included city or state, setting, study years, study design,

population studied, number of subjects, number of samples, culture and identification

methods, vaccination coverage, prevalence or incidence of disease, PHiD-CV efficacy or

effectiveness, percent change, and serotype distribution.

7. Pneumococcal Disease Surveillance in Brazil

Pneumococcal Disease Surveillance in Brazil is performed at the national level by SINAN

(Sistema de Informação de Agravos de Notificação), which includes meningitis as a notifiable

disease. Additionally, in the state of São Paulo, the CVE (Centro de Vigilancia

Epidemiologica) collects meningitis data, including cases confirmed as caused by

pneumococcus. Pneumococcal isolates from hospitals throughout Brazil are submitted to a

national reference laboratory at the Adolfo Lutz Institute, São Paulo. Before the

implementation of the PHiD-CV in the national immunization program, the Brazilian

Ministry of Health invited state health secretariats in ten states (Amazonas, Bahia, Ceara, the

Federal District, Goiás, Minas Gerais, Paraná, Pernambuco, Rio Grande do Sul, and São

Paulo) from the 5 regions to identify hospitals to participate in an enhanced surveillance of

invasive pneumococcal disease. Ministry of Health distributed information for blood cultures

indications and provided necessary laboratory supplies. The methods of detection were also

improved with the introduction of real-time PCR in three of the ten states (Bahia, Goiás, and

São Paulo). Notification of pneumonia and otitis are not mandatory at the national level but

data can be collected at the city or state levels. In DATASUS (governmental open-access

public health database system), the absolute number of hospitalizations in the public system

can be classified by the main diagnosis at admission according to the International

Classification of Diseases version 10 (Hospital Morbidity database).

SUPPLEMENTARY APPENDIX B

SUPPLEMENTARY DATA

Table S1. Number of cases and incidence rate of meningitis in Brazil according to the

national and São Paulo registers.

2007 2008 2009 2010 2011 2012 2013 2014SINAN (Brazil) - Meningitis (Number of cases)

Children <1 year-oldS. pneumoniae 231 230 221 185 156 112 118 117

N. meningitidis B 682 653 673 552 505 493 473 462

MM+MCC 719 803 831 910 940 804 646 513

All agesS. pneumoniae 1037 1073 1052 1103 1214 1107 1077 949

N. meningitidis B 3596 3474 3348 2980 3140 3147 2875 2793

MM+MCC 81 84 79 97 80 63 49 62

CVE (São Paulo) - Meningitis (Incidence/100,000)Children <2 years-old

Overall 22.9 24.5 26.4 31.6 18.8 13.9 12.2 12.1

S. pneumoniae 9.7 9.3 8.5 8.5 5.4 5.3 5.9 6.0

H. influenzae B (<1 year-old)

2.43 1.03 1.6 3.0 3.16 3.14 2.77 3.14

All agesOverall 2.75 3.15 2.98 3.5 3.27 2.79 2.31 1.75

S. pneumoniae 1.0 1.1 0.9 1.2 1.2 1.1 1.1 1.0

H. influenzae B 0.08 0.08 0.08 0.12 0.13 0.17 0.11 0.12

Data were obtained from the websites of the Notifiable diseases information system (SINAN)

and Centro de Vigilância Epidemiológica (CVE) “Alexandre Vranjac” in São Paulo [4, 5].

MM+MMC, cases of meningococcemia with meningococcal meningitis.

Figure S1. Indirect effect of PHiD-CV on vaccine-type IPD (A), overall IPD and

pneumococcal meningitis (B), and pneumonia (C) in unvaccinated children and adults.

*Statistically significant change; IPD, invasive pneumococcal disease; ns, not statistically

significant.

References

[1] PubMed. Available from: http://www.ncbi.nlm.nih.gov/pubmed. Accessed: 11 Mar 2016.

[2] Embase. Available from: http://www.embase.com/. Accessed: 01 Dec 2015.

[3] SciELO (Scientific Electronic Library Online). Available from: http://www.scielo.br/.

Accessed: 01 Dec 2015.

[4] Sistema de Informação de Agravos de Notificação (SINAN). Meningite - Casos confirmados

notificatdos no Sistema de Informaçao de Agravos de Notificaçao - Sinan net. 2015; Available from:

http://dtr2004.saude.gov.br/sinanweb. Accessed: 01 December 2015.

[5] Centro de Vigilância Epidemiológica (CVE) “Alexandre Vranjac”. Meningites: Coeficientes

de incidência (por 100.000 hab), Estado de São Paulo, 1998 a 2015. 2015; Available from:

http://www.cve.saude.sp.gov.br/htm/resp/meni_dados.html#. Accessed: 01 Dec 2015.

[6] Jokinen J, Rinta-Kokko H, Siira L, Palmu AA, Virtanen MJ, Nohynek H, et al. Impact of ten-

valent pneumococcal conjugate vaccination on invasive pneumococcal disease in Finnish children--a

population-based study. PLoS One 2015;10(3):e0120290. doi: 10.1371/journal.pone.0120290

[7] Nuorti JP, Rinta-Kokko H, Toropainen M, Siira L, Virtanen MJ, Nohynek H, et al. Invasive

pneumococcal disease among adults after routine infant conjugate vaccination in Finland -

implications for vaccination policy. 9th International Symposium on Pneumococci and Pneumococcal

Diseases (ISPPD-9); Hyderabad, India; 2014.

[8] dos Santos SR, Passadore LF, Takagi EH, Fujii CM, Yoshioka CR, Gilio AE, et al. Serotype

distribution of Streptococcus pneumoniae isolated from patients with invasive pneumococcal disease

in Brazil before and after ten-pneumococcal conjugate vaccine implementation. Vaccine

2013;31(51):6150-4. doi: 10.1016/j.vaccine.2013.05.042

[9] Brandileone MCC, Almeida SCG, Zanella RC, Guerra MLLS, Bokermann S, Prado LS, et al.

Effect of PCV10 vaccination on pneumococcal serotypes in Brazil using the national pneumococcal

laboratory network surveillance. 9th International Symposium on Pneumococci and Pneumococcal

Diseases (ISPPD-9); Hyderabad, India; 2014.

[10] Azevedo J, Soares Santos M, Santos Galvão V, Cunegundes Escobar E, Vilasboas R,

Machado Cordeiro S, et al. The burden of invasive pneumococcal disease among older patients in the

era of conjugate vaccine. 9th International Symposium on Pneumococci and Pneumococcal Diseases

(ISPPD-9); Hyderabad, India; 2014.

[11] Andrade AL, Minamisava R, Policena G, Cristo EB, Domingues CM, de Cunto Brandileone

MC, et al. Evaluating the impact of PCV-10 on invasive pneumococcal disease in Brazil: A time-

series analysis. Hum Vaccin Immunother 2016;12(2):285-92. doi: 10.1080/21645515.2015.1117713.

[12] Andrade AL, Afonso ET, Cristo EB, Morais-Neto OL, Policena G, Toscano CM, et al. Overall

and indirect effect of PCV10 on pneumonia hospitalizations in children in Brazil after 3 years of

vaccination. 33rd Annual Meeting of the European Society for Paediatric Infectious Diseases

(ESPID); Leipzig, Germany; 2015.

http://www.cve.saude.sp.gov.br/htm/resp/meni_dados.html

http://dtr2004.saude.gov.br/sinanweb

http://www.scielo.br/

http://www.embase.com/

http://www.ncbi.nlm.nih.gov/pubmed

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