» Burden of influenza illness in HIV-infected population

» Immunogenicity of influenza vaccines in HIV-infected adults

» Efficacy of trivalent influenza vaccine (TIV) in HIV-infected adults

» Immunogenicity of influenza vaccines in HIV-infected children

» Efficacy of TIV in HIV-infected children

» Studies on TIV in HIV-infected and HIV-uninfected pregnant women for protection of mothers and young infants

• Potential for more severe infection than age-matched HIV-uninfected people (Pre-ART) (Madhi , PIDJ, 2002)

• In children <2 years in South Africa, severe influenza-associated pneumonia, 8-fold higher (Pre-ART)

(Madhi, J Ped, 2000)

• In South Africa and the USA adults with AIDS experience a elevated risk of influenza-associated death, 150–200-fold higher than that in the general population of the same age and 2–4-fold higher than that in adults aged ≥65 years

(Cohen, CID, 2012)

Limited data on burden and epidemiology of influenza in developing countries

Adapted from: Kunisaki et al. Lancet Infect Dis, 2009, 9: 493-504

Reference Data source Population Data available Outcome N of outcomes per 1000 person-years in disease-positive population (95% CI)

N of outcomes per 1000 person-years in control (95% CI)

Thompson, JAMA, 2003

National Center for Health Statistics database

General population

.. Influenza-associated deaths

NA All ages: 0·03; 65 years or older: 0·22

Thompson, JAMA, 2004

National hospital discharge survey

General population

.. Influenza-associated hospital admissions

NA All ages: 0·52; 65 years or older: 2·81

Neuzil, JAMA, 1999

Tennessee Medicaid database (women 15–64y for HIV and for controls)

HIV, pre-HAART

1 725 712 person-years of data

Combined, excess hospital admissions and deaths

1973–93: 33·4 0·4

Lin, Arch Intern Med, 2001

National Center for Health Statistics database (13y or older for AIDS, 25–54y for controls)

AIDS, pre-HAART

149 256 person-years of data

Excess deaths from pneumonia or influenza during influenza seasons

1991–92: 1·26 (1·07–1·45); 1992–93: 1·47 (1·28–1·65); 1993–94: 0·94 (0·80–1·08)

0·01 (0·009–0·01); 0·009 (0·009–0·01); 0·009 (0·008–0·009)

Neuzil, J AIDS, 2003

Tennessee Medicaid database (HIV positive, 15–50 years)

HIV, post-HAART

7368 person-years of data

Excess hospital admissions Excess deaths

1995–96, pre-HAART: 48 (16–81); 1996–99, post-HAART: 5 (−0·5–11); 0·5 (−4·8–5.7)

NA

Vilchez, AJT, 2002

University of Pittsburgh transplant programme database

Organ transplant

3569 organ transplants over 10 years

Hospital admissions

Lung transplant: 4·18–41·8 Liver transplant: 0·28–2·8 Kidney transplant: 0·43–4·3

NA

• Post-ART, influenza-related mortality in adults with AIDS dropped 3–6-fold but remained elevated compared with the general population (all-cause RR, 44)

(Cohen, CID, 2012)

Susceptibility to H1N1p infection and severity of influenza illness were not increased in HIV-infected adults without advanced immunosuppression or comorbid conditions (Peters, CID, 2011; Isais, J Infect, 2010)

HOWEVER more frequent and rapid use of neuraminidase inhibitors in HIV-infected patients diagnosed with pH1N1 compared to the general population (Martinez, HIV Med, 2011; Perez, AIDS, 2010)

The risk of influenza-related complications, was increased in those with

advanced immunosuppression or high-risk comorbid conditions (Ormsby, AIDS, 2010) HAART, undetectable HIV RNA and early administration of oseltamivir were

associated with improved survival

In South Africa: >50% of deaths from H1N1 in 2009 had underlying HIV infection 91 deaths - 32 HIV status was known - 17(53%) HIV infected 25 deaths (28%) in pregnant women - 14 HIV status was known - 10 HIV infected (Archer, Euro Surveill, 2009; Moodley , SAMJ, 2011)

Multiple studies have shown lower antibody responses in HIV-infected compared with the uninfected control group (Amendola, J Med Virol, 2001; Zanetti, Vaccine, 2002; Ragni, J Lab Clin Med, 1987; Nelson, AIM, 1988; Kroon, AIDS, 1998; Brydak, Clin Drug Invest; Yamanaka, J AIDS, 2005; Evison, CID, 2009)

AIDS << Asymptomatic HIV << HIV-uninfected

Most of these studies are limited by small sample sizes (particularly for very low CD4 cell counts)

Seroconversion rates (a) and seroprotection rates (b) in HIV-infected and HIV-uninfected former drug addicts vaccinated against influenza

Group 1 HIV+ CD4<200

Group 2 HIV+ CD4 200-500

Group 3 HIV+ CD4>500

Group 4 HIV-

64% of HIV+ on ART

From: Zanetti et al. Vaccine, 2002, B29-B32

Inflexal V 1998-99 season, single dose

CD4 cell counts >200/mL

HIV viral load (Evison et al. CID, 2009; 48: 1402-12 Yamanaka et al. J Acquir Immune Defic Syndr, 2005; 39: 167-73)

Young age and shorter duration of HIV infection (Crum-Cianflone et al. CID, 2011; 52: 138-146)

Predictors of Influenza Vaccine immune response in HIV-infected patients

From: Kunisaki et al. Lancet Infect Dis, 2009, 9: 493-504

Nelson 1988

Miotti 1989

Iorio 1997

Kroon 1998

Brydak 1999

Amendola 2001

Zanetti 2002

CD4+ <200 CD4+ 200–500 CD4+ >500 Healthy control

0 20 40 60 80 100

% with postvaccination protective H3N2 titers

Reference Country

Vaccine N CD4+ count VL BDL, %

ART, % SC rates SP rates

Iorio et al., Vaccine, 1997 Italy

1993-94 Vaxigrip 15 mg/HA BOOSTER

50 HIV+ 76 HIV-

Stratified by CD4 56.9%

100% if CD4 <500

-

HIV+ CD4+>500 ≈ HIV-: ≥70% for H3N2 HIV+ CD4+<500: ≤38 % for H3N2 Booster had no effect

Durando et al., Clin Vacc Imm, 2008 Italy

2005-06 Agrippal vs. MF56 adj (Fluad) 15 mg/HA

95 HIV+ 161 HIV-# 398 72%

H1N1: 41% nadj; 45% adj H3N2: 45% nadj; 54% adj* B: 47% nadj; 48% adj

70-85% with SP at baseline H1N1: 94% nadj; 90% adj H3N2: 86% nadj; 94% adj* B: 94% nadj; 90% adj

Cooper et al., PlosOne, 2011 Canada

2008-09 Fluviral 15 mg/HA SD+SD DD+DD SD

298 HIV+ <200: 9% 76%

89%

H1N1: 37%DD; <22%SD H3N2: <48% B: <25% Post-booster H1N1: 36% DD; <27%SD H3N2: <41% B: <22%

H1N1: <44% H3N2: <73% B: <50% Post-booster H1N1: <42% H3N2: <57% B: <39%

McKittrick et al., Ann Int Med, 2012 USA

2010-11 Fluzone 15 mg/HA vs. 60 mg/HA

195 HIV+ 438 88%

89%

H1N1: 59% SD; 75% HD H2N3: 54% SD; 78% HD B: 35% SD; 56% HD

≈50% with SP at baseline H1N1: 87% SD; 96% HD H2N3: 92% SD; 96% HD B: 80% SD; 91% HD

Gelinck et al., Vaccine, 2009, The Netherlands

2005-06 Influvac 15 mg/HA IM. vs. 3 mg/HA ID

80 HIV+ 41 HIV-

440 80% ID similar immune response as compared to IM HIV- better response

Seroconversion (SC) and Seroprotection (SP) rates at aprox 1 month after vaccination *After adjusting for prevaccination titers (Beyer method) significant better response with Fluad # HIV- results not presented here. HIV- subjects mounted a stronger response than HIV+ for all strains

Reference Country

Vaccine N CD4+ cell count

VL below detection, %

ART, % SC rates SP rates

Tebas et al., AIDS, 2010 USA

MIV, 15 mg HA

120 502 91.7%

99% 56% 25% with SP titers at baseline 71% (61% of H1N1 naïve)

Crum-Cianflone et al CID, 2011 Vaccine, 2011

MIV, 15 mg HA

65 HIV+ 66 HIV-

581 56.9%

82% Day 28: 54% HIV+; 75% HIV- Month 6: 28% HIV+; 56% HIV-

T0 >1:10: 27% HIV+; 44% HIV- * Day 28: 68% HIV+; 83% HIV- Month 6: 43% HIV+; 73% HIV-

Yanagisawa et al., Vaccine, 2011 Japan

MIV, 15 mg HA

182 HIV+ 42 HIV-

411 85.7%

93% 39% HIV+; 86% HIV- 13% with SP at baseline (HIV+/-) 50% HIV+; 86% HIV- #

El Sahly et al., JID, 2012

MIV, 15mg vs. 30mg HA BOOSTER

192 HIV+ <200: 37%; ≥200: 63%

>87% Day 21: 48% (sd); 69% (dd) Day 31: 53% (sd); 71% (dd) Month 6: 29% (sd); 46% (dd)

Day 21: 56% (sd); 73% (dd) Month 6: 43% (sd); 59% (dd)

Seroconversion (SC) and Seroprotection (SP) rates at aprox 1 month after vaccination if not indicated *All participants regardless of baseline titers # Significance not shown

HAI seroconversion and seroprotection rates (95% CI) after vaccination with 15 μg or 30 μg HA for the study population and stratified by CD4 cell count

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From: El Sahly H M et al. J Infect Dis. 2012;205:703-712

Reference Country

Vaccine N CD4+ count VL BDL, %

ART, %

SC rates SP rates

Bickel et al., AIDS, 2010 Germany

Split virion, 3.75mg HA, AS03 adj

160 HIV+ 514 69.4%

90% 68.8% 75%

Tremblay et al., Vaccine, 2011 Canada

Split virion, 3.75mg HA AS03 adj

84 HIV+ 427 74%

83% 44% 45%

Bickel et al., CID, 2011 Germany

Split virion, 3.75mg HA AS03 adj (booster)

135 HIV+ 514 68.2%

90% Day 21: 68.2% Day 42: 92%

Day 21: 73% Day 42: 97%

Cooper et al., CROI, 2011 Canada

MIV, 3.75mg HA AS03 adj (booster)

150 HIV+ 519 84%

Day 21: 74% Day 42: 86% (b); 66% (nb) Month 6: 32% (b); 22% (nb)

Day 21: 80% Day 42: 94% (b); 73% (nb) Month 6: 44% (b); 36% (nb)

Manuel et al., CID, 2011 Switzerland

Split virion, 3.75mg HA AS03 adj (booster HIV+)

30 HIV+ 30 HIV-

587 97%

100% - Day 0: 13% HIV+; 3% HIV- Day 21: 80% HIV+; 70% HIV- Day 49: 93% HIV+; 80% HIV-

Launay et al., JID, 2011 France

MIV, 15mg nadj vs. 3.75mg AS03 adj (booster)

306 HIV+ 229 76%

77%* Day 21: 89% (adj); 71% (nadj)#

Day 42: 97% (adj); 87% (nadj) Day 21: 93% (adj); 76% (nadj) Day 42: 99% (adj); 92% (nadj)

S-Oliveira et al., PlosOne, 2012 Brazil

Split virion, AS03 adj 3.75mg vs. 7.5mg (booster HIV+)

256 HIV+ 71 HIV-

550 65%

80% Day21: 47%(sd); 52%(dd);75%HIV- Day42: 77%(sd); 84%(dd);72%HIV-

Day 21: 71%(sd); 76% (dd);82%HIV- Day 42: 84%(sd); 88%(dd);82% HIV- Month6: 78%(sd); 85% (dd);95%HIV-

Fabbiani et al., Vaccine, 2011 Italy

MIV, 7.5mg HA MF59 adj

41 HIV+ ≤200: 10%; >500: 54% 87.8%

83% 61% 78%

Kajaste-Rudnitski etal., AIDS, 2011

MIV, 7.5mg HA MF59 adj

44 HIV+ 148 HIV-

563 77.3%

36.4% HIV+; 79.0 % HIV- 97.7% HIV+; 98% HIV-

Soonawala et al PlosOne, 2011

MIV, 7.5mg HA MF59 adj (booster)

57 HIV+ 44 HIV-

507 79%

91% Day 21: 53% HIV+; 73% HIV- # Day 56: 63% HIV+; 70% HIV-

D0: 44% HIV+; 23% HIV- # Day 21: 88% HIV+; 93% HIV- Day 56: 91% HIV+; 89% HIV-

*Stratification done by ART treatment # Significance not shown

After 3.75mg HA AS03 adj booster SC ≥86% SP ≥93% ≈ HIV-

DD effect in >40 yrs or nadir CD4 <200cell/ml

After 7.5mg HA MF59 adj SC 36-63% SP 78-98% Booster little effect

RCT, 102 participants, military clinic, USA

Risk difference

-.75 -.5 -.25 0 .25

Study

Risk difference

(95% CI)

No. of events

Treatment Control

Tasker (1999) -0.26 (-0.39,-0.13) 1/55 13/47

Fine (2001) -0.17 (-0.40, 0.06) 19/42 18/29

Yamanaka (2005) -0.15 (-0.25,-0.05) 16/262 14/66

Ranieri (2005) -0.48 (-0.63,-0.34) 12/90 34/55

Overall -0.27 (-0.42,-0.11) 48/449 79/197

Meta-analysis of Effectiveness of Influenza Vaccine in HIV-infected Adults (N=646)

Protective vaccine Not protective vaccine

Heterogeneity chi-squared = 14.23 (d.f. = 3), p = 0.003, I2 = 76.8% Test of RD=0: z = 2.28, p = 0.004

Observational, 71 participants, residential facility outbreak, USA

Prospective observational cohort, 328, Japan

Prospective observational PPV/TIV, 145, Italy

From: Atashili J et al. BMC Infect Dis, 2006, 6 (138): 1-6

Efficacy and immunogenicity of TIV in HIV-infected adults: RTC

Baseline demographic and clinical information for the study cohort included in the ITT analysis

TIV

N=255

Placebo

N=251

Total follow up time (person/weeks) 5003.9 4906.1

Mean Age (SD) years 36.3 (7.2) 36.4 (7.2)

Female : Male 5:1 6:1

Proportion on ARV % (n) 67% (175) 69% (174)

Median CD4 (IQR) 340 (243 – 473) 356 (245- 512)

Surveillance for ILI Laboratory testing for Influenza TIV 2008 southern hemisphere formulation (vaccination: April-June2008)

From: Madhi S.A et al.; Clin Infect Dis; 2011; 52: 138

From: Madhi S.A et al.; Clin Infect Dis; 2011; 52: 138

a

From: Madhi S.A et al.; Clin Infect Dis; 2011; 52: 138

12 Influenza cases in placebo recipients (11 H1N1 + 1 Flu B)

3 Influenza cases in TIV recipients (H1N1)

Reference Country

Age Vaccine N CD4 count VL BDL, %

ART, %

SC rates SP at vacc SP rates

Zuccotti et al., JIMR, 2004 Italy

7.2±3.7 yrs 1999-2000 Virosomal Inflexal V (0.5 ml)

23 HIV+ 1038 78% H1N1: 57% H3N2: 74% B: 52%

H1N1: 0% H3N2: 26% B: 13%

H1N1: 57% H3N2: 83% B: 61%

Levin et al., Vaccine, 2008

12 (5-18) yrs 2004-05 LAIV vs. Fluozone (0.5 ml)

243HIV+ Stratified by CD4 >70%

100% H1N1: 32 - 33% H3N2: 14 - 44% B: 11 - 34%

H1N1: 42 - 46% H3N2: 78 - 88% B: 23 - 37%

H1N1: 63 - 67% H3N2: 92 - 96% B: 33 - 69%

Montoya et al MIOC, 2007 Colombia

4.6±2.5 yrs Imovax (0.5 or 0.25ml) 2 doses, 1 mth apart

16 HIV+ vs. 10 HIV-

1202 56%

100% H1N1: 69 - 70% H3N2: 50 – 50% B: 44 - 70%

H1N1: 19 - 30% H3N2: 13 - 70% B : 13 - 30%

H1N1: 69 - 71%* H3N2: 43 - 67% B: 50 - 71%

Kosalaraksa et al., Vaccine, 2011 Thailand

11 (8.7-12.6) yrs

2008-09 TIV-Sanofi Pasteur (0.5 ml) 2 doses, 1 mth apart

127HIV+ vs. 21 HIV-

92%

H1N1: 81- 81% H3N2: 71 - 81% B: 43 - 52% Post-booster H1N1: 89 - 100% H3N2: 84 - 81% B: 49 - 62%

H1N1: 43 - 62% H3N2: 38 - 76% B: 6 - 14%

H1N1: 89 - 86% H3N2: 85 - 100% B: 48% - 67% Post-booster H1N1: 95 - 100% H3N2: 95 - 100% B: 55 - 71%

Hakim et al., Vaccine, 2011 USA

18±4 yrs MIV 15mg HA 2 doses, 1 mth apart

39 HIV+ 625 46%

69% Day 56: 63% Day 56: 92%

Esposito et al., Vaccine, 2011 Italy

15±4 yrs

MIV 7.5 mg HA MF59 adj Virosomal Inflexal V simultaneously or sequentially #

36 HIV+ vs. 36 HIV-

200-500:17%; >500: 83% 83.3%

97.2%

Day 28: 94 -100% Day56: 100-100% H1N1: 77 -94%** H3N2: 53 - 94% B: 12 - 88%

47 - 47% H1N1: 29 - 29% H2N3: 59 - 59% B: 0 - 0%

Day28:100-100% Day56:100-100% H1N1: 82 - 88% H3N2: 82 - 88% B: 18 - 88%

Palma et al., Biological, 2012 Italy

15(3-21) yrs MIV 7.5 mg HA MF59 adj 2 doses, 1 mth apart

83 HIV+ vs. 37 HIV-

760 83%

98% Day 21: 60 - 82% Day 42: 73 - 89%

64 - 54%

Day21:100-100% Day42:100-100%

Seroconversion (SC) and Seroprotection (SP) rates at aprox 1 month after vaccination * Only children without protective titers at baseline # Data from sequentially arm not shown here. GMTs higher in the simultaneous arm ** percentages at day 28 only.

Booster effect ≈HIV-

MF59 adj better immuno ≈HIV-

Efficacy and immunogenicity of TIV in HIV-infected children: RTC

TIV

N=206

Placebo

N=204

Total follow up time H3N2 (weeks) 2579.1 2576.7

Median Age (range) months 23.1 (6.0-59.9) 24.0 (6.0-59.8)

6-<36 months % (n) 79.1% (163) 72.6% (148)

Female : Male 1.5:1 1.1:1

Median weight (range) 10.9 (5.4 – 23.9) 10.9 (5.8 – 19.5)

Breastfed % (n) 16.5% (34) 20.1% (41)

Proportion on ARV % (n) 92.2% (190) 91.7% (187)

Median CD4+ count (IQR) 1770.0 (464-4390) 1648.0 (491-4615)

Median CD4+ % (range) 33.5 (16.3 – 59.7) 33.4 (15.2- 54.0)

Children received 2 doses of TIV or placebo 1 month apart (0.5ml/dose if ≥36 months or 0.25ml if younger)

TIV 2009 southern hemisphere formulation (vaccination: Feb-May 2009) Immunogenicity measures 1-month after 2nd dose Surveillance for ILI Laboratory testing for Influenza

Madhi SA et al. AIDS, 2012, 26

Baseline demographic and clinical information for the study cohort included in the ITT analysis

Seroconversion rate to vaccine strains in TIV in HIV-infected vaccine and placebo recipients

0

10

20

30

40

50

60

70

80

90

100

Perc

en

tag

e w

ith

sero

-

co

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H1N1 H3N2 Influenza B

TIV; n=40 Placebo, n=43

P<0.001 P<0.001

P<0.001

Madhi SA et al. AIDS; 2012; 26

Madhi SA et al. AIDS, 2012, 26

P=0.025

P=0.005

P=0.013

Poor immunogenicity against the dominant wt-circulating strain, particularly in the younger age-group

From: Madhi SA et al. AIDS, 2012, 26

From: Madhi SA et al. AIDS, 2012, 26

AA changes in key positions in 3 HA epitopes. Evidence of drift in reference to the vaccine strain.

Influenza vaccines induce a T cell-dependent process (humoral immunity). The

depletion of T-helper cell in HIV infection leading to inadequate T-cell signalling

can cause vaccination failure.

HIV infection is also associated with deficiencies in CMI.

HIV-infected individuals manifest an immune response to influenza vaccination

that, while not as vigorous as that of healthy controls, probably confers some level of

clinical protection against influenza and, does so without causing excess harm.

Vaccination new strategies

Increasing the among of antigen (more robust response by improving

dendritic cell uptake and subsequent signalling of B and T-cells)

Increasing the number of doses

Adjuvant vaccine

Alternative routes of vaccination

Stimulating the immune system with a different vaccine strategy

(e.g. DNA prime-protein boost)