Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: von Gottberg A, de Gouveia L, Tempia S, et al. Effects of vaccination on invasive pneumococcal disease in South Africa. N Engl J Med 2014;371: DOI: /NEJMoa (PDF updated June 9, 2016.)

2 Supplementary Appendix Table of Contents 1.1 List of collaborators Methods Tables and figures References

3 1.1 List of collaborators GERMS-SA (Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa) Sandeep Vasaikar, Dania Perez (Eastern Cape); Eugene Elliot, Ute Hallbauer (Free State); Alan Karstaedt, Jeannette Wadula, Charl Verwey, Kathy Lindeque, Charlotte Sriruttan, Sharona Seetharam, Charles Feldman, Trusha Nana, Norma Bosman, Sheeba Varughese, Adrian Duse, Warren Lowman, David Moore, Maomokgethi Moshe, Kamaldeen Baba, Theuns Avenant, Nicolette du Plessis, Gary Reubenson, Ranmini Kularatne, Maphoshane Nchabeleng, Anwar Hoosen, Bonnie Maloba, Ruth Lekalakala (Gauteng); Yacoob Coovadia, Koleka Mlisana, Moherndran Archary, Ramola Naidoo, Khatija Dawood, Fathima Naby, Khine Sweswe, Prathna Bhola, Prasha Mahabeer, Lisha Sookan, Praksha Ramjathan, Halima Dawood, Sumayya Haffejee (Kwa-Zulu Natal); Ken Hamese, Takalani Muditambi (Limpopo) Greta Hoyland, Jacob Lebudi, Barry Spies (Mpumalanga); Stan Harvey, Pieter Jooste, Eunice Weenink (Northern Cape); Andrew Rampe, Lino Sono (North West); Elizabeth Wasserman, Preneshni Naicker, Andrew Whitelaw, Brian Eley, James Nuttal, Louise Cooke, Heather Finalyson, Helena Rabie, Collleen Bamford, Heidi Orth, Mark Nicol, Rena Hoffmann, Steve Oliver (Western Cape); Keshree Pillay, Chetna Govind, (LANCET); Adrian Brink, Maria Botha, Inge Zietsman, Inge Zietsman, Suzy Budavari, Xoliswa Poswa, Mark Cruz da Silva, Jennifer Coetzee (AMPATH); Marthinus Senekal (PATHCARE); Chris van Beneden, Stephanie Schrag, Elizabeth Zell, Anne Schuchat, Tom Chiller, Angela Ahlquist, Fred Angulo,(CDC); Keith Klugman, (Emory); Anne von Gottberg, Linda de Gouveia, Karen Keddy, Arvinda Sooka, Nelesh Govender, Jaymati Patel, Vanessa Quan, Susan Meiring, Melony Fortuin-de Smidt, Mohlamme John Mathabathe, Claire von Mollendorf, John Frean, Desiree du Plessis, Bhavani Poonsamy, Olga Perovic, Marshagne Smith, Cheryl Cohen, Penny Crowther, Jabulani Ncayiyana, Relebohile Ncha, Languta Sibiya, Sonwabo Lindani, Nevashan Govender, Nireshni Naidoo, Babatyi Kgokong, Vusi Nokeri (NICD). 2

4 1.2 Methods PCV introduction PCV7 (Prev[e]nar, manufactured by Pfizer, formerly Wyeth Pharmaceuticals) was registered in South Africa in PCV7 became available in the national, public-sector vaccine program from April PCV7 was recommended using a 3-dose schedule: two primary infant doses at 6 and 14 weeks aligned to the Expanded Program on Immunization (EPI) visits, and a booster at 9 months, aligned with the measles dose in the EPI. Children born after 15 February 2009 (6 weeks old or younger on 1 April 2009) were eligible for PCV7; no catch-up vaccination of older children was undertaken until 2011, when children who had received 2 or more doses of PCV7 received a PCV13 dose at 18 months. Between April-June 2011, gradually all provinces replaced PCV7 with PCV13. Invasive pneumococcal disease surveillance Surveillance for IPD began in 1999, 1 but was enhanced for quality and completeness in 2003 through GERMS-SA (Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa), a nationwide, active, laboratory-based surveillance system. In 2012, over 200 laboratories (representing more than 450 hospitals, Table S1) sent reports of laboratory-confirmed IPD together with isolates to the National Institute for Communicable Diseases (NICD) in Johannesburg. All clinical microbiology laboratories throughout the country are encouraged to report. The number of hospitals and laboratories covered by our surveillance increased over the years (Table S1), however, 94% (32,922/35,192) of cases were reported from 150 hospitals, and >70% of these hospitals reported cases for the full 8-year period. Demographic details (age, gender, date of specimen collection, and body fluid source of isolate) were recorded from all hospitals. Enhanced surveillance at 24 sentinel hospitals located in all nine provinces 3

5 collected additional information including admission date, HIV serological status, discharge diagnosis and outcome; these hospitals accounted for almost 50% of all reported cases nationally. Annual laboratory audits throughout the study period using a laboratory-based information system (Disa*Lab Laboratory Information Management System) for all public-sector laboratories was used to identify unreported cases. We added the cases identified by audit to the database and were used in rate calculations. Trends in IPD by HIV status The proportion of IPD cases with known HIV status at the enhanced surveillance sites increased from 70% in 2005 to 91% in 2012 for children <2 years of age and from 69% in 2005 to 88% in 2012 for individuals years of age. Early in the study period ( ), HIV testing in children with IPD was mainly prompted by clinical indicators, while from 2008 through 2012 HIV testing was performed more systematically among all children admitted with pneumococcal disease regardless of HIV symptoms, 2 leading to improvement in estimates of HIV prevalence among cases over time. To estimate the HIV status among individuals not tested for HIV at enhanced sites from 2008 to 2012, we first used chained equations multiple imputation 3 (over 10 imputation runs). The predictors for the multiple imputation model were age, gender, province, year and serotype category (e.g. PCV7, 6A, additional PCV13 and non PCV serotypes). We then estimated the age, year and serotype-category specific relative risk (RR) for IPD hospitalizations due to HIV infection from 2008 to 2012 using the imputed dataset (enhanced sentinel site cases only). The RR for IPD hospitalization due to HIV infection was estimated by dividing the rate of IPD HIV-infected cases to the rate of IPD HIV-uninfected cases in each of the above mentioned categories. The rates of IPD hospitalizations by HIV status were obtained by dividing the estimated number of IPD HIV-infected and uninfected cases in each category by the population at risk. The midyear estimates of HIV-positive and -negative individuals in the population were estimated using 4

6 THEMBISA. 4 Subsequently, we estimated the number of HIV-positive and -negative individuals among the total (national) number of IPD cases (including not-enhanced sites) by age, year and serotype category from 2008 to 2012 using the following formula: IPD HIV 1 PopHIV 1 1 * RR * PopHIV IPD Total [1] IPD HIV+ is the age-, year- and serotype-category specific national number of IPD HIV-positive cases, Pop HIV+ and Pop HIV- are the age- and year-specific number of HIV-positive and -negative individuals in the population respectively, RR is the age-, year- and serotype-category specific relative risk for IPD hospitalization due to HIV infection calculated from the enhanced sentinel sites as described above and IPD Total is the age-, year- and serotype-specific national number of IPD hospitalizations. To obviate the potential biases in the HIV seroprevalence among IPD cases from 2005 to 2007 for the reasons provided above we estimated the age-, year- and serotype category-specific number of HIV-positive and -negative individuals among the national number of IPD cases using the formula in equation 1, but we used the age- and serotype-category specific HIV RR estimated for This was under the assumption of constant RR of IPD hospitalization due to HIV infection from 2005 to 2008 given the minimal changes of antiretroviral treatment (ART) coverage in the population over this period. 4, 5 For this calculation we opted to use the HIV RR instead of the HIV prevalence among IPD cases in 2008 because of the changing HIV prevalence in the population from 2005 to

7 1.3 Tables and figures Table S1: Number of laboratories and hospitals reporting by year to GERMS-SA (Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa) and percentage coverage of all health facilities nationally Number of % reporting to Number of laboratories Number of hospitals hospitals in South GERMS-SA Year reporting reporting (n) Africa* (N) (n/n) *Combination of private and public sector facilities; for years with missing data, the previous year s data was used. 6 6

8 Figure S1: Percentage of viable isolates available by year and age, for cases of invasive pneumococcal disease reported in South Africa, 2005 through % 90% Percentage viable isolates 80% 70% 60% 50% 40% 30% 20% 10% 0% 2005 (N=4886) 2006 (N=4736) All ages <2 years years 2007 (N=4743) 2008 (N=4835) 2009 (N=4765) Year of surveillance 2010 (N=4199) 2011 (N=3804) 2012 (N=3224) 7

9 Table S2. Rate changes of invasive pneumococcal disease cases among children <2 years of age, by year and serotype, South Africa, 2011 and 2012 compared with baseline years PCV7 was introduced in 2009 and PCV13 in Number and rate (cases per 100,000 personyears) Change in rate (baseline vs baseline 2012 vs baseline average) Serotypes n Rate n Rate n Rate Rate difference# (95% CI*) % change (95% CI) Rate difference# (95% CI) % change (95% CI) All (-36.9 to-29.4) -60 (-65 to-56) (-41.4 to-34.2) -69 (-72 to -65) PCV7 vaccine (-28.4 to -23.1) -80 (-84 to -76) (-31.3 to -26.2) -89 (-92 to -86) (-1.1 to -0.1) -63 (-86 to -14) -0.9 (-1.4 to -0.5) -91 (-99 to -63) 6B (-6.6 to -4.0) -76 (-83 to -65) -6.8 (-7.9 to -5.6) -97 (-99 to -92) 9V (-2.0 to -0.8) -86 (-96 to -64) -1.5 (-2.1 to -1) -94 (-99 to -78) (-9.4 to -6.6) -87 (-92 to -80) -8.7 (-10 to -7.2) -94 (-97 to -90) 18C (-1.9 to -0.6) -75 (-90 to -47) -1.5 (-2 to -0.9) -86 (-96 to -65) 19F (-6.1 to -3.9) -88 (-93 to -79) -4.2 (-5.3 to -3.1) -74 (-83 to -61) 8

10 23F (-5.4 to -3.1) -70 (-80 to -58) -5.1 (-6.2 to -4.0) -85 (-91 to -75) Serotype 6A (-5.2 to -2.6) -62 (-73 to -47) -5.4 (-6.5 to -4.2) -85 (-91 to -76) PCV13 vaccine (-3.2 to -0.1) -22 (-39 to -1) -4.3 (-5.7 to -2.9) -57 (-68 to -42) (-0.1 to +0.4) -19 (-54 to +40) -0.8 (-1.5 to -0.2) -57 (-79 to -16) (-0.6 to +0.2) -33 (-75 to +68) -0.3 (-0.7 to +0.2) -41 (-79 to +54) (-0.2 to +0.9) +32 (-36 to +67) +0.2 (-0.3 to +0.7) +22 (-60 to +63) 7F (-0.3 to +0.02) -100 (-100 to +130) -0.1 (-0.3 to +0.02) -100 (-100 to +132) 19A (-2.6 to -0.2) -31 (-51 to -5) -3.2 (-4.2 to -2.1) -70 (-81 to -55) Nonvaccine (-3.5 to -0.6) -20 (-36 to -0.2) +0.5 (-1.3 to +2.4) +6 (-16 to +23) 7C (-0.5 to +0.2) -28 (-79 to +137) (-0.4 to +0.4) -4 (-69+ to 193) (-0.3 to +1.1) +26 (-27 to +58) +0.5 (-0.2 to +1.2) +31 (-20 to +60) 9N (-0.6 to +0.1) -48 (-84 to +55) -0.1 (-0.5 to +0.3) -21 (-71 to +109) 12F (-0.3 to +0.8) +27 (-51 to +66) (-0.5 to +0.5) -4 (-58 to +118) (-0.4 to +0.4) -4 (-69 to +194) -0.2 (-0.6 to +0.6) -64 (-94 to +50) 15B (-0.8 to +0.2) -36 (-72 to +41) +0.2 (-0.4 to +0.8) +22 (-50 to +60) (-0.5 to +0.2) -40 (-85 to +108) -0.1 (-0.5 to +0.2) -28 (-79 to +137) Other (-2.8 to -0.5) -36 (-54 to -11) +0.2 (-1.0 to +1.5) +5 (-27 to +29) 9

11 # cases per 100,000 population; *CI, confidence interval; ^ average rate for period PCV=pneumococcal conjugate vaccine 10

12 Table S3. Rate changes of invasive pneumococcal disease cases among adults 25 to 44 years of age, by year and serotype, South Africa, 2005 through PCV7 was introduced in 2009 and PCV13 in Number and rate (cases per 100,000 personyears) Change in rate (baseline vs baseline 2012 vs baseline average) Serotypes n Rate n Rate n Rate Rate difference# (95% CI*) % change (95% CI) Rate difference# (95% CI) % change (95% CI) All (-3.0 to -1.5) -18 (-24 to -13) -4.0 (-4.7 to -3.3) -34 (-39 to -29) PCV7 vaccine (-1.8 to -1.0) -37 (-45 to -28) -2.1 (-2.5 to -1.8) -57 (-63 to -50) (-0.3 to +0.04) -18 (-38 to +7) -0.3 (-0.5 to -0.1) -36 (-52 to -15) 6B (-0.4 to -0.08) -44 (-62 to -18) -0.4 (-0.5 to -0.3) -75 (-86 to -60) 9V (-0.3 to -0.04) -45 (-65 to -13) -0.2 (-0.3 to -0.1) -59 (-76 to -33) (-0.5 to -0.2) -62 (-75 to -44) -0.5 (-0.6 to -0.3) -76 (-85 to -62) 18C (-0.1 to +0.09) -5 (-44 to +60) -0.1 (-0.2 to -0.07) -71 (-87 to -39) 19F (-0.3 to +0.02) -27 (-50 to +7) -0.2 (-0.3 to -0.04) -40 (-60 to -10) 11

13 23F (-0.5 to -0.2) -43 (-59 to -22) -0.4 (-0.6 to -0.3) -58 (-71 to -41) Serotype 6A (-0.2 to +0.2) -3 (-26 to +28) -0.4 (-0.5 to -0.2) -46 (-61 to -26) PCV13 vaccine (-0.7 to +0.2) -7 (-18 to +5) -1.1 (-1.5 to -0.2) -32 (-40 to -22) (-0.4 to +0.2) -6 (-23 to +14) -0.5 (-0.7 to -0.2) -33 (-46 to -17) (-0.3 to +0.05) -20 (-43 to +12) -0.2 (-0.3 to -0.04) -35 (-55 to -8) (-0.07 to +0.08) +3 (-101 to +54) -0.6 (-0.1 to +0.01) -50 (-80 to +21) 7F (-0.2 to +0.02) -37 (-66 to +16) (-0.1 to -0.08) -10 (-48 to +56) 19A (-0.2 to +0.3) +2 (-22 to +21) -0.4 (-0.6 to -0.1) -31 (-45 to -12) Nonvaccine (-1.0 to -0.1) -15 (-25 to -4) -0.4 (-0.9 to ) -11 (-21 to +4) (-0.3 to -0.03) -34 (-54 to -6) -0.2 (-0.3- to 0.03) -33 (-53 to -5) 7C (-0.07 to +0.09) +7 (-86 to +54) (-0.05 to +0.1) +21 (-53 to +60) 9N (-0.1 to +0.09) -5 (-44 to +62) (-0.07 to +0.1) +14 (-42 to +49) 10A (-0.1 to +0.06) -17 (-57 to +60) ( to +0.1) +6 (-73 to +49) 12F (-0.1 to +0.2) + 5 (-29 to +31) +0.2 (-0.01 to +0. 3) +23 (-3 to +43) (-0.03 to +0.2) +33 (-20 to +63) (-0.04 to +0.1) +27 (-31 to +60) 15B (-0.07 to +0.1) +12 (-63 to +53) (-0.07 to +0. 1) +13 (-59 to +53) 16F (-0.09 to +0.1) +10 (-42 to +44) (-0.1 to +0.1) -5 (-41 to +52) 12

14 17F (-0.1 to +0.04) -29 (-65 to +40) (-0.1 to +0.08) -5 (-41 to +52) 22F (-0.07 to +0. 1) +13 (-64 to +54) +0.5 (-0.04 to +0.1) +26 (-35 to +60) (-0.07 to +0.04) -27 (-69 to +68) (-0.07 to +0.07) +2 (-109 to +54) Other (-0.7 to -0.2) -34 (-48 to -18) -0.6 (-0.8 to -0.4) -44 (-56 to -30) # cases per 100,000 person-years; *CI, confidence interval; ^ average rate for period PCV=pneumococcal conjugate vaccine 13

15 Table S4. Rate changes of invasive pneumococcal disease cases among children and adults, by HIV, year and serotype, South Africa, 2005 through PCV7 was introduced in 2009 and PCV13 in Number and rate (cases per 100,000 population) Change in rate vs baseline 2012 vs baseline (average baseline) Serotypes n Rate n Rate n Rate Rate difference# % change Rate difference# % change (95% CI*) (95% CI) (95% CI) (95% CI) < 2 years HIV negative All (-14.7 to -8.9) (-49 to -33) (-16.9 to -11.2) (-56 to -42) PCV vaccine (-13.2 to -9.3) (-79 to -66) (-14.9 to -11.2) (-89 to -79) 6A (-2.2 to -0.3) (-62 to -10) (-3.2 to -1.5) (-88 to -59) PCV

16 vaccine (-0.9+ to 1.7) (-24 to +32) (-2.6 to -0.3) (-53 to -7) Nonvaccine (-1.1 to +1.9) (-21 to +28) (+1.2 to +4.5) (+15 to +48) HIV positive All ( to ) (-72 to -58) ( to ) (-83 to -70) PCV vaccine ( to ) (-83 to -69) ( to ) (-91 to -78) 6A (-72.5 to -27.9) (-82 to -39) (-84.7 to -43.7) (-95 to -62) PCV vaccine (-52.2 to -0.7) (-60 to +3) (-77.3 to -32.4) (-88 to -44) Nonvaccine (-56.1 to -4.7) (-63 to -3) (-52.7 to +4.0) (-59 to +11) years HIV negative 15

17 All (-0.2 to +0.3) (-22 to +22) (-0.4 to +0.1) (-29 to +13) PCV vaccine (-0.3 to +0.02) (-58 to +9) (-0.4 to -0.07) (-72 to -19) 6A (-0.1 to +0.05) (-75 to +109) (-0.1 to +0.02) (-88 to +46) PCV vaccine (-0.1 to +0.2) (-11 to +42) (-0.02 to +0.1) (-42 to +36) Nonvaccine (-0.04 to +0.3) (-11 to +50) (-0.02 to +0.3) (-7 to +51) HIV positive All (-14.3 to -8.2) (-29 to -18) (-21.2 to -15.3) (-43 to -33) PCV vaccine (-7.6 to -4.3) (-48 to -30) (-10.4 to -7.3) (-65 to -52) 6A (-0.9 to +0.7) (-28 to +27) (-2.2 to -0.7) (-62 to -27) 16

18 PCV vaccine (-3.4 to +0.02) (-0.3 to +23) (-6.6 to -3.5) (-45 to -27) Nonvaccine (-5.2 to -1.7) (-31 to -11) (-4.7 to -1.2) (-28 to -8) PCV=pneumococcal conjugate vaccine; PCV7 serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F; PCV13 serotypes: PCV7 serotypes plus 1, 3, 5, 7F, 19A; 6A is analyzed separately. 17

19 Cases per 100,000 person-years All disease PCV-7 serotypes Serotype 6A Additional PCV-13 serotypes Non PCV-13 serotypes (N*=159) 2006 (N=144) 2007 (N=154) 2008 (N=156) 2009 (N=154) 2010 (N=109) 2011 (N=103) 2012 (N=103) Time (years) Figure S2. Rates of invasive pneumococcal disease among infants <10 weeks# of age, by serotype group and year, South Africa, 2005 through PCV7 and PCV13 were introduced in 2009 and 2011, respectively. * N=number of cases of IPD reported in this age group each year. # We evaluated children <10 weeks for possible indirect effects of PCV. The age group <10 weeks was chosen because among children one month after the 6-week PCV dose a low proportion (~20-30%) had seroprotective titers to the majority of serotypes 7 and one dose at 6 weeks demonstrated poor effectiveness in a nested case-control study. 8 18

20 A 1.6 Cases per 100,000 person-years All disease PCV-7 serotypes Serotype 6A Additional PCV-13 serotypes Non PCV-13 serotypes Time (years) B 60 Cases per 100,000 person-years All disease PCV-7 serotypes Serotype 6A Additional PCV-13 serotypes Non PCV-13 serotypes Time (years) Figure S3. Rates of invasive pneumococcal disease among A) HIV-negative and, B) HIV-positive adults 25 to 44 years of age, by serotype group and year, South Africa, 2005 through PCV7 and PCV13 were introduced in 2009 and 2011, respectively. 19

21 A 5.0 Cases per 100,000 person-years Penicillin Ceftriaxone Multidrug resistance Time (years) B 40.0 Cases per 100,000 person-years Penicillin Ceftriaxone Multidrug resistance Time (years) Figure S4. Rates of disease caused by nonsusceptible pneumococcal isolates among A) all ages, and B) among children <2 years of age, by antimicrobial agent and year, South Africa, 2005 through PCV7 and PCV13 were introduced in 2009 and 2011, respectively. 20

22 1.4 References 1. Huebner RE, Klugman KP, Matai U, Eggers R, Hussey G. Laboratory surveillance for Haemophilus influenzae type b, meningococcal, and pneumococcal disease. Haemophilus Surveillance Working Group. S Afr Med J 1999;89(9): Meyers T, Dramowski A, Schneider H, Gardiner N, Kuhn L, Moore D. Changes in pediatric HIVrelated hospital admissions and mortality in Soweto, South Africa, : light at the end of the tunnel? J Acquir Immune Defic Syndr 2012;60(5): White IR, Royston P, Wood AM. Multiple imputation using chained equations: Issues and guidance for practice. Stat Med 2011;30(4): Johnson LF. University of Cape Town, Faculty of Health Sciences, School of Public Health and Family Medicine, Research, Centre for Infectious Disease Epidemiology and Research, Publications: THEMBISA version A model for evaluating the impact of HIV/AIDS in South Africa. Available at: Accessed February Johnson LF. Access to antiretroviral treatment in South Africa, The South African Journal of HIV Medicine 2012;(43): Health Systems Trust. Number of Health Facilities (Health System Trust: Health Status Indicators web site]. Available at: Accessed April Madhi SA, Izu A, Violari A et al. Immunogenicity following the first and second doses of 7-valent pneumococcal conjugate vaccine in HIV-infected and -uninfected infants. Vaccine 2013;31(5): Cohen C, von Mollendorf C, de Gouveia L et al. Effectiveness of seven-valent pneumococcal conjugate vaccine (PCV7) against invasive pneumococcal disease HIV-infected and -uninfected children in South Africa: a matched case-control study. Clin Infect Dis 2014;accepted. 21