Adjuvanted influenza a (H1N1) 2009 vaccine in patients with hematological diseases: good safety and immunogenicity even in chemotherapy-treated patients

ORIGINAL ARTICLE

Adjuvanted influenza a (H1N1) 2009 vaccine in patients withhematological diseases: good safety and immunogenicityeven in chemotherapy-treated patientsHonar Cherif1, Martin H€oglund1, Karlis Pauksens2

1Department of Medical Sciences, Section of Hematology, Uppsala University Hospital, Uppsala; 2Department of Infectious Diseases, Uppsala

University Hospital, Uppsala, Sweden

Abstract

Background: Patients with hematological malignancies are more susceptible to viral infections including

influenza. In 2009, the World Health Organization classified the novel influenza A (H1N1) virus as

pandemic. The potential impact of this pandemic for patients with hematological disorders was unknown.

Institutional guidelines recommended two doses of AS03-adjuvanted influenza A (H1N1) 2009 pandemic

vaccine for these patients. Objectives: We aimed to determine the safety, immunogenicity, and clinical

efficacy of this vaccine in patients with hematological diseases. Furthermore, we compared the

immunological responses to that obtained by the non-adjuvanted trivalent seasonal influenza vaccine (TIV).

Methods: All included patients received adjuvanted pandemic vaccine and the majority received TIV.

Serum for antibody analyses was collected at five time points. Results: Thirty-one patients with different

hematological diseases were included. After the second vaccine dose, a total of 25 (81%) reached both

protective levels of antibodies and seroconversion response. Antibody titers � 1 : 40 persisted for 50%

of responding patients at 1 yr. Seroconversion was observed in 69% of 14 patients who had undergone

hematopoietic stem cell transplantation and in all (9/9) patients with myeloma (five with ongoing treatment

including high-dose corticosteroids). After vaccination with TIV, seroconversions against the three included

strains were detected in 28%, 40%, and 20%. Response to the adjuvanted pandemic vaccine was

superior (P < 0.009). Conclusions: A substantial proportion of patients with hematological malignancies

including patients undergoing chemotherapy mounted a good response to the adjuvanted pandemic

vaccine. This vaccine had superior immunogenicity as compared to the non-adjuvanted TIV.

Key words pandemic H1N1; influenza A H1N1; hematological diseases; hematological malignancies; influenza vaccine; vaccine;

immunocompromised

Correspondence Honar Cherif, MD, PhD, Department of Hematology 50C, Uppsala University Hospital, Uppsala SE 791 85,

Sweden. Tel: +46 18 611 9125; Fax: +46 18 611 5650; e-mail: [email protected]

Accepted for publication 19 February 2013 doi:10.1111/ejh.12094

Patients with hematological malignancies are at increasedrisk of serious infectious disease complications(1, 2). Beingimmunocompromised, they are more susceptible to viralinfections including influenza, which may in these patientsbe associated with prolonged illness and viral shedding andincreased morbidity and mortality (3–6). The primaryapproach to the prevention of influenza is vaccination.

As results from clinical trials are inconsistent, uncertaintyexists between hematologists regarding the benefit of influ-enza vaccination in patients with hematological

malignancies. Immunological responses as low as 5% and ashigh as 75% have been reported (3, 7–11). Moreover, thereare unjustified concerns regarding the safety of influenzavaccines in immunocompromised patients. Today, annualvaccination against seasonal influenza is provided in Swedenfor high-risk patients including those with hematological dis-eases.In April 2009, a novel influenza A (H1N1) strain was

detected in Mexico (12). The World Health Organizationclassified the transmission as pandemic in June 2009 [WHO,

© 2013 John Wiley & Sons A/S 1

European Journal of Haematology

Pandemic Influenza A (H1N1) strain, update-14, 21 October2009] The impact of this viral infection on patients withhematological disorders was unknown, and there were con-cerns about the risk of serious complications. Institutionalguidelines, in accordance with recommendations by theEuropean Medicines Agency and the UK Department ofHealth, recommended the injection of two doses of adjuvant-ed inactivated H1N1 vaccine with a minimum of 3 wkbetween doses for patients with hematological malignancies.Being an adjuvanted vaccine, it was expected that the influ-enza A (H1N1) 2009 vaccine would give a stronger immuneresponse in comparison with the non-adjuvanted seasonalinfluenza vaccine.We conducted a prospective study to determine the safety,

immunogenicity, and clinical efficacy of AS03 adjuvantedinfluenza A (H1N1) 2009 pandemic vaccination in patientswith hematological diseases. Furthermore, we compared theimmunological responses to that obtained following trivalentseasonal influenza vaccination. We aimed to facilitate thedevelopment of evidence-based vaccination guideline in thisgroup of patients.

Materials and methods

Patients with different hematological diseases who were trea-ted as outpatients at the Department of Hematology, UppsalaUniversity Hospital, Uppsala, during the pandemic periodwere included in the study. Patient characteristics are shownin Table 1. All included patients received the AS03-adjuvant-ed pandemic influenza A (H1N1) 2009 vaccine and the major-ity received the seasonal trivalent influenza vaccine (TIV).The pandemic influenza vaccine PandemrixTM from Glaxo-SmithKline was given (intramuscular injections in the deltoidmuscle in the non-dominant arm) in two doses 4 wk apart(day 0 and 28). The split virion vaccine contained 3. 75 lg ofhemagglutinin antigen from the inactivated influenza A/Cali-fornia/7/2009 (H1N1)-derived strain and the AS03 AdjuvantSystem composed of squalene (10.69 mg), DL-a-tocopherol(11.86 mg), and polysorbate 80 (4.86 mg). The seasonal TIVwas given on day 56, that is, 4 wk after the second dose of thepandemic vaccine. It was a non-adjuvanted vaccine containing15 lg of hemagglutinin from each of the correspondingstrains A/Brisbane/59/2007 (H1N1)-like virus; A/Brisbane/10/2007 (H3N2)-like virus (A/Brisbane/10/2007 or A/Uruguay/716/2007 vaccine virus), and B/Brisbane/60/2008-like virus.Demographic data, clinical characteristics, and informationregarding vaccine-related adverse events were collected byself-reporting and review of medical records up to a minimumof 1 yr after last study vaccination.

Serology

Serum for antibody analyses was taken at baseline (day 0)and on days 28, 56, and at 1 yr from baseline. In patients

receiving seasonal influenza vaccination, a serum antibodyconcentration was also taken on day 86. All available bloodsamples were analyzed for the pandemic strain and for thethree influenza strains in the seasonal influenza vaccine ateach time point.The assays for measurement of antibody response were

performed by GSK Biologicals. All serum samples wereblinded. The antibody titers against the strains in the pan-demic and seasonal influenza vaccine were measured using avalidated hemagglutination inhibition (HI) assay as describedby the WHO Collaborating Center for Influenza, Centers forDisease Control and Prevention (Hehme NW et al., ClinDrug Invest 2002). Briefly the serum samples were treatedby enzymatic treatment and heated to destroy non-specificinhibitors. Hemagglutination was performed in a microtitertest using chicken erythrocytes with the A/California/7/2009(H1N1) strain as antigen for the pandemic vaccine andA/Brisbane/59/2007H1N1 and A/Uruguay/716/2007 (H3N2)strains as antigens for the seasonal influenza vaccine. HIassays were performed in duplicate for each sample using

Table 1 Clinical characteristics of 31 patients with hematological dis-

eases receiving adjuvant influenza A (H1N1) 2009 vaccine and triva-

lent seasonal influenza vaccine

Characteristics

Age in years, median (range) 57 (18–84)

Male/female 15/16

Underlying disease1

Acute myelogenous leukemia 6 (18)

Non-Hodgkin lymphoma 2 (6)

Multiple myeloma 9 (29)

Chronic lymphocytic leukemia 5 (16)

Acute lymphoblastic leukemia 2 (6)

Chronic myelogenic leukemia 2 (6)

Myeloproliferative neoplasm 1 (3)

Aplastic anemia 1 (3)

Thalassemia, stem cell transplanted 1 (3)

Osler’s disease on systemic therapy 1 (3)

AL amyloidosis 1 (3)

High-dose chemotherapy with stem cell support1 13 (41)

Allogeneic 8 (25)

Autologous 5 (16)

Ongoing anti-infection prophylaxis1

Trimethoprim–sulfamethoxazole 13 (41)

Valaciclovir 11 (35)

Fluconazole 2 (6)

Ongoing immunosuppressive therapy1

Cyclosporine A 8 (24)

Corticosteroids 10 (31)

Prior chemotherapy1 24 (77)

Within 1 yr 20 (62)

Within 3 months 15 (48)

Chemotherapy and immunosuppression na€ıve1 5 (16)

Mortality

One year 1 (3)

Three months 0

1Number (%).

2 © 2013 John Wiley & Sons A/S

Adjuvanted influenza vaccine in patients with hematological diseases Cherif et al.

serial 2-fold dilutions with a starting dilution of the treatedserum of 1 : 10. The sample titer was the highest dilutionthat completely inhibited hemagglutination. Titers below thedetection limit of 1 : 10 were assigned a value of 1 : 5 inthe calculations. An HI titer � 40 was regarded as protec-tive against influenza infection and defined as seroprotection.The response to vaccination (seroconversion) was defined

as at least a fourfold increase in antibody titer after vaccina-tion or if prevaccination HI titer was <10 a postvaccinationtiter of HI � 40 or greater.In the HI assay used for the influenza B/Brisbane/60/

2008-like virus, the B viruses were split with ether treat-ment, while the A strains were not. Due to this treatment, Btiters are usually higher than A titers and not comparable.Accordingly, only seroconversion is a reliable indicator forimmune response to influenza B vaccination.

Statistics

Data were expressed by mean (standard deviation, SD) or asmedian (range). In the calculations, the antibody titers wereexpressed as geometric mean titers (GMT) before and aftervaccination. In comparison between or within different patientgroups, the nonparametric tests Mann–Whitney U-test, chi-squared test, Wilcoxon signed rank test, paired sign test, Fish-er’s exact test, and simple regression test were used whenappropriate. A P-value � 0.05 was considered significant.The study was approved by the Regional Ethics Commit-

tee and performed in compliance with Good Clinical Prac-tice guidelines and the Declaration of Helsinki. Writteninformed consent was obtained from all participants.

Results

Thirty-four patients with different hematological diseaseswere initially included in the study during the period Octo-ber to December 2009. Three patients were excluded fromfurther analysis: One patient with acute myelogenous leuke-mia (AML) developed the pandemic influenza disease 5 dafter the first dose of vaccine and two patients with chroniclymphocytic leukemia (CLL) who were on regular immuno-globulin substitution for several years because of hypo-gammaglobulinemia and severe invasive pneumococcaldisease. Clinical characteristics of the 31 patients included inthe study are summarized in Table 1. None of the includedpatients were treated with rituximab. Proportion of patientson chemotherapy or immunosuppression did not differbetween vaccination dose 2 and the TIV vaccine.

Immunogenicity of the influenza vaccines

On day 0, that is, immediately prior to vaccination with thepandemic influenza A (H1N1) 2009 vaccine, one patient hadprotective level of antibodies to A (H1N1) 2009

(HI titer � 40) and three had low levels of antibodies (HItiters between 10 and 20). At day 28 (4 wk after the firstdose of vaccine), a total of 16 (52%) patients had protectivelevels of antibodies to A (H1N1) 2009 and 15 (48%) had se-roconverted (Table 2). Four weeks after the second dose ofthe pandemic vaccine (day 56), a total of 25 (81%) reachedboth protective levels of antibodies and seroconversion. Atyear one and before vaccination for the next influenza sea-son 2010/2011, serum levels of antibodies were available for18 patients. Protective levels of antibodies against A (H1N1)2009 retained in 9 (50%) of these patients (Table 2).Twenty-five patients were vaccinated with seasonal TIV

on day 56. Pre-existing protective antibodies (HI titer � 40)were found in 4 (16%) to A/Brisbane/59/2007 H1N1-likevirus, 7 (28%) to A/Uruguay/10/2007/H3N2-like virus, and13 (52%) to B/Brisbane/60/2008-like virus. The GMT at day0 and 56 for the two influenza A strains did not differ sig-nificantly. Four weeks after vaccination with seasonal influ-enza vaccine (sample taken on day 84), protective antibodylevels and seroconversion responses were detected againstA/Brisbane/59/2007 H1N1-like virus in 10 (40%) respective7 (28%) patients, against A/Uruguay/10/2007/H3N2-likevirus in 14 (56%) respective 10 (40%) patients, and againstB/Brisbane/60/2008-like virus in 19 (76%) respective 5(20%) patients (Table 2). These rates of seroconversion afterthe seasonal TIV were not different from that after the firstdose of the influenza A (H1N1) 2009 vaccine (chi-squareand Fisher’s exact tests). However, after the second dose ofinfluenza A (H1N1) 2009 vaccine, the response was better(81%) than that to the three influenza strains in the TIV(chi-square and Fisher’s exact tests, P < 0.001, P < 0.009and P < 0.001, respectively) (Fig. 1).At 1 yr, antibody levels were analyzed in 16 patients who

were vaccinated with seasonal influenza vaccine and 1 (6%),5 (31%), and 5 (31%) had HI titers � 40 to the three TIVstrains, respectively. Five (83%) of six patients lost their se-roprotective antibody levels to A/Brisbane/59/2007 H1N1-like virus, 4 (44%) of 9 to A/Uruguay/10/2007/H3N2-likevirus, and 9 (64%) of 14 to B/Brisbane/60/2008-like virus.The GMT at 1 yr was approximately as low as that beforevaccination for the two influenza A strains included in theseasonal influenza vaccine (the GMT for the influenza Bstrain was comparable with day 0). In contrast, the GMT forthe pandemic strain remained greater with a factor of 3.5(Table 2). The two patients with CLL who were excludedfrom the study due to ongoing prophylaxis with regularimmunoglobulin infusions showed no pre-existing antibodiesand did not develop any measurable antibodies to influenzaA (H1N1) 2009 after vaccination (data not shown).

Immunogenicity in different subgroups

Among 13 patients who had undergone either allogeneic(n = 8) or autologous (n = 5) hematopoietic stem cell


Cherif et al. Adjuvanted influenza vaccine in patients with hematological diseases

transplantation (HSCT), a total of 9 (69%) patients devel-oped protective antibody levels and had a seroconversionresponse after two doses of the pandemic vaccine. Nine ofthe HSCT-treated patients were recently transplanted (i.e.HSCT within 5 months before vaccination) and 5 (56%) ofthem responded to the pandemic vaccine with seroconver-sion and developed protective antibodies.Eleven patients among the 13 HSCT-treated patients were

vaccinated with the seasonal influenza vaccine within thestudy. Two of these patients (2/11) had seroconversionresponse to A/Brisbane/59/2007 H1N1-like virus, whereasnone of the seven who underwent HSCT within 1–5 monthsresponded. The corresponding figures for A/Uruguay/10/2007/H3N2-like strain were four of 11 and two of seven,respectively, and for B/Brisbane/60/2008-like strain weretwo of 11 and one of seven, respectively.Nine patients with multiple myeloma at different stages of

disease progression were included in the study. Their mediandisease duration was 48 months (range 4–120). Five patientswith myeloma had ongoing treatment with regimens

Table 2 Immunogenicity of influenza A (H1N1) 2009 and the three strains of the seasonal influenza vaccine in patients with hematological dis-

eases.

VaccinationAll patientsA/Calif A/Calif + TIV1

A/BriH1N1

A/UruH3N2 B/Bri

Day 0, n 31 25 25 25 25

GMT 5.9 6.2 8.4 11.0 16.5

Range 5–40 5–40 5–80 5–226 5–640

HI titer � 40, n (%) 1 (3) 1 (4) 3 (12) 7 (28) 6 (24)

Day 28, n 31 25 25 25 24

GMT 32.3 32.9 10.0 11.2 25.2

Range 5–640 5–640 5–113 5–160 5–640

HI titer � 40, n (%) 16 (52) 13 (52) 4 (16) 7 (28) 10 (38)

Factor increase GMT 5.5 5.3 1.2 1.0 1.5

Seroconversion, n (%) 15 (48) 13 (52) 1 (4) 0 (0) 2 (8)

Day 56, n 31 25 25 25 25

GMT 130.8 121.3 10.4 11.7 35.8

Range 5–2560 5–2560 5–226 5–226 5–640

HI titer � 40, n (%) 25 (81) 20 (80) 4 (16) 7 (28) 13 (52)


Seroconversion, n (%) 25 (81) 20 (80) 1 (4) 0 (0) 2 (8)

Day 86, n 25 25 25 25 25

GMT 71.6 71.6 24.3 37.8 76.7

Range 5–1280 5–1280 5–640 5–2560 5–1280

HI titer � 40 n (%) 18 (72) 18 (72) 10 (40) 14 (56) 19 (76)


Seroconversion, n (%) – – 7 (28) 10 (40) 5 (20)

One year, n 18 16 16 16 16

GMT 22.4 21.8 7.9 16.1 22.3

Range 5–160 5–160 5–40 5–160 5–435

HI titer � 40 n (%) 9 (50) 8 (50) 1 (6) 5 (31) 5 (31)


A/Calif, A/California/7/2009(H1N1) vaccine; A/Bri, A/Brisbane/59/2007 H1N1-like virus vaccine; A/Uru, A/Uruguay/716/2007 vaccine; B/Bri, B/Bris-

bane/60/2008-like virus vaccine.1Patients vaccinated with both A (H1N1) 2009 and trivalent influenza vaccine (TIV); n, number; GMT, geometric mean titers; HI, hemagglutination

inhibition.

Figure 1 Number of patients with hematological diseases (among 25

included patients) with protective antibody levels (HI titer > 40) to

influenza A (H1N1) 2009 vaccine (given day 0 and 28) and seasonal

influenza vaccine (given day 56) over time. For influenza B, serocon-

version is used. A/Calif, influenza A (H1N1) 2009 vaccine; A/Bri,

A/Brisbane/59/2007 H1N1-like virus; A/Uru, A/Uruguay/10/2007/H3N2-

like virus; B/Bri, B/Brisbane/60/2008-like.



including high-dose corticosteroids (in combination withbortezomib, thalidomide, melphalan, or lenalidomide) at timeof vaccination, three of the remaining patients with myelomawere treated with autologous SCT, and one was chemother-apy naïve. Seroconversion was found in four patients withmyeloma (44%) after the first influenza A (H1N1) 2009 vac-cination and in all nine (100%) after the second dose. Theseroconversion rates to seasonal influenza vaccination inpatients with myeloma were two (22%) to the two influenzaA strains and one (11%) to the B strain.

Safety

Both vaccines were well tolerated, and no serious adverseevents were reported. No patient developed signs or symp-toms of influenza during the follow-up period.

Discussion

In this prospective study, we demonstrate a good safety andimmunological response to the adjuvanted influenza A(H1N1) 2009 vaccine even in heavily immunocompromisedpatients with hematological malignancies.The use of influenza vaccines in patients with hematologi-

cal malignancies has been under discussion for many yearsdespite the availability of well-designed clinical studies (7,9, 13–16). Contradicting results from studies give rise touncertainty about safety and efficacy between treating clini-cians. Studies vary with regard to type of influenza vaccineused, intensity of chemotherapy, and timing of vaccinationin relation to disease stage and completion of chemotherapy.In this study, a significant proportion of included patientsresponded to the influenza A (H1N1) 2009 vaccine.Responses were seen even in patients with ongoing immuno-suppression, recently completed chemotherapy, and recentlyundergone HSCT. These results strengthen the notion thatannual influenza vaccination of immunocompromisedpatients is justified.This study included nine patients with long-time multi-

ple myeloma, of which eight were heavily treated(recently undergone HSCT or ongoing high-dose cortico-steroid-containing regimens). Interestingly, all thesepatients responded developing protective HI levels andseroconversion. To our knowledge, this is the first timethe efficacy of the two-dose influenza A (N1H1) 2009vaccine is reported in patients with myeloma. The findingthat these responded significantly better to the adjuvantedvaccine than to the seasonal influenza vaccine indicatesthat adjuvanted vaccines should be used in patients receiv-ing intense immunosuppressive therapies. Furthermore,more than half of patients who were recently (within 1–5 months) treated with HSCT responded to the pandemicvaccine. Our results together with those recently reportedby Engerhard et al. in HSCT recipients motivate early

post-transplant vaccination of these high-risk patients incase of influenza epidemics and pandemics (17).Suboptimal immunogenicity of influenza vaccines includ-

ing different H1N1 vaccines in patients with hematologicalmalignancies has been reported in many studies (18). Theseresults encouraged the idea of giving booster doses of thevaccine to improve response. In a randomized study byLjungman et al., two doses of seasonal influenza vaccinewere compared with one dose and no improvement inresponses was seen (16). Meanwhile, Lavallade et al. usedadjuvanted influenza vaccine and demonstrated a significantimprovement in seroprotection rates after the second vaccinedose (19). Similar results are reported in human immunodefi-ciency virus–infected individuals, who also represent apotentially immunocompromised group (20–22). In the cur-rent study, the second dose of the vaccine improved bothimmunological responses and seroconversion rates even inheavily chemotherapy-treated patients. The adjuvanted natureof the vaccine may explain this discrepancy as adjuvants canincrease the immunogenicity of a vaccine (23). We had theopportunity to compare adjuvanted with a non-adjuvantedinfluenza vaccine in the same cohort of immunocompro-mised patients. Notably, the adjuvanted vaccine was moreimmunogenic and could achieve significantly higher sero-conversion rates. Waddington et al. compared the immuno-genicity of adjuvanted split virion influenza H1N1 vaccinewith non-adjuvanted whole virion in children and reportedsimilar outcome (24). These results indicate the potential forimproving influenza vaccination effects in this group ofpatients using adjuvanted vaccines. The safety and efficacyof the two-dose regimens in the current study support therecommendations given by our local expert group, the Euro-pean Medicines Agency and the UK Department of Health,to give two doses of the adjuvanted vaccine to immunocom-promised patients. However, rapid decay in the protectiveantibody levels may indicate the need to further boosterdoses of the vaccine for optimal coverage over en entireinfluenza season in this patient population. Clinical trials areneeded to explore this suggestion.Our study has limitations. The study size is small, no

healthy controls were included, and a heterogeneous groupof patients with varying hematological diagnoses and degreeof immunosuppression are included. These limitations arerelated to the opportunistic nature of the study and the shorttime for recruitment during the pandemic period. We findthe result worth sharing as the findings in this study are ofinterest for the health community and can pave the way forlarger randomized studies in the future.Serological responses and protective titers are considered

as reliable surrogate markers for the clinical response to vac-cinations (10). However, the definition of the protectivetiters is derived from healthy individuals and it is unknownwhether they can be applied on immunocompromisedpatients. The quality of evidence supporting the clinical



efficacy of influenza vaccine in patients with hematologicalmalignancies is low (25). Therefore, for a more accuratemapping of the efficacy of influenza vaccines, the clinicalprotective effect needs to be studied in larger trials withlong-time follow-up. In this study, no patient developedinfluenza after the vaccination. However, this finding needsto be interpreted carefully, as the incidence of influenza A(H1N1) was very low in Sweden during the pandemicperiod.At the start of the study, it was unclear whether the sea-

sonal influenza vaccine could boost the response to the pan-demic vaccine or vice versa and whether the vaccinesshould be given concomitantly or sequentially. We startedwith the pandemic vaccine that was most urgent. No cross-reactivity with increased antibody titers to the influenza Astrains in the seasonal influenza vaccine after pandemicinfluenza vaccination was seen. Neither was there anincrease in the pandemic antibody titers after seasonal influ-enza vaccination. These findings indicate that no boostingeffects are to be expected in case of sequential vaccination(adjuvanted seasonal or vice versa).In conclusion, a substantial proportion of patients with

hematological malignancies including even heavily treatedpatients with myeloma mounted a good response to an adju-vanted influenza A (H1N1) 2009 vaccine. This vaccine wassafe and well tolerated and had a superior immunogenicitythan that of the non-adjuvanted seasonal influenza vaccine.The use of adjuvanted vaccines may be the way to improveresponse to influenza vaccination in patients with hematolog-ical diseases.

Financial support

The assays for measurement of antibody response to vacci-nation were performed by GlaxoSmithKline Biologicals.

Conflicts of interest

GlaxoSmithKline Biologicals performed the assays for mea-surement of antibody response to vaccination. All serumsamples were blinded.

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Adjuvanted influenza a (H1N1) 2009 vaccine in patients with hematological diseases: good safety and immunogenicity even in chemotherapy-treated patients