Trial Outcomes & Findings for Efficacy Against TB Disease, Safety, and Immunogenicity of MVA85A/AERAS-485 in HIV-Infected Adults (C-030-485) (NCT NCT01151189)

Last Updated: 2016-05-24

Results Overview

The primary objective of this study is to evaluate the safety of MVA85A/AERAS-485 compared to placebo in HIV-infected, African adult subjects without active TB disease.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

650 participants

Primary outcome timeframe

Adverse Events (AEs) are recorded for 28 days post vaccination, Serious Adverse Events (SAEs) for at least 6 months post second vaccination.

Results posted on

2016-05-24

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo The placebo is a licensed product manufactured by Allermed, Inc. and is used for evaluation of delayed-type of hypersensitivity reactions in adults. Placebo: Subjects were to receive an intradermal injection placebo on Study Day 0, followed 6-9 months later by a booster injection of placebo.	MVA85A/AERAS-485 MVA85A/AERAS-485 is a recombinant modified vaccinia virus Ankara expressing the M. tuberculosis antigen, Ag85A. Dosage of the study vaccine to be administered will be 1x10\^8 pfu. MVA85A/AERAS-485: Subjects received intradermal injection of MVA85A/AERAS-485 on Study Day 0, followed 6-9 months later by a booster injection of MVA85A/AERAS-485.
Overall Study STARTED	326	324
Overall Study Received Vaccine	325	324
Overall Study COMPLETED	311	314
Overall Study NOT COMPLETED	15	10

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Efficacy Against TB Disease, Safety, and Immunogenicity of MVA85A/AERAS-485 in HIV-Infected Adults (C-030-485)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=325 Participants Placebo: Subjects were to receive an intradermal injection placebo on Study Day 0, followed 6-9 months later by a booster injection of placebo.	MVA85A/AERAS-485 n=324 Participants MVA85A/AERAS-485 is a recombinant modified vaccinia virus Ankara expressing the M. tuberculosis antigen, Ag85A. Dosage of the study vaccine to be administered will be 1x10\^8 pfu. MVA85A/AERAS-485: Subjects received intradermal injection of MVA85A/AERAS-485 on Study Day 0, followed 6-9 months later by a booster injection of MVA85A/AERAS-485.	Total n=649 Participants Total of all reporting groups
Age, Continuous	37.8 years STANDARD_DEVIATION 6.61 • n=5 Participants	37.7 years STANDARD_DEVIATION 6.69 • n=7 Participants	37.7 years STANDARD_DEVIATION 6.65 • n=5 Participants
Sex: Female, Male Female	255 Participants n=5 Participants	265 Participants n=7 Participants	520 Participants n=5 Participants
Sex: Female, Male Male	70 Participants n=5 Participants	59 Participants n=7 Participants	129 Participants n=5 Participants
Race/Ethnicity, Customized Black	304 participants n=5 Participants	302 participants n=7 Participants	606 participants n=5 Participants
Race/Ethnicity, Customized Coloured	21 participants n=5 Participants	22 participants n=7 Participants	43 participants n=5 Participants
Race/Ethnicity, Customized White	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Race/Ethnicity, Customized Asian	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants
Region of Enrollment Senegal	179 participants n=5 Participants	178 participants n=7 Participants	357 participants n=5 Participants
Region of Enrollment South Africa	146 participants n=5 Participants	146 participants n=7 Participants	292 participants n=5 Participants

PRIMARY outcome

Timeframe: Adverse Events (AEs) are recorded for 28 days post vaccination, Serious Adverse Events (SAEs) for at least 6 months post second vaccination.

Population: Safety: All randomized subjects who received a dose of study vaccine, based on actual treatment received.

The primary objective of this study is to evaluate the safety of MVA85A/AERAS-485 compared to placebo in HIV-infected, African adult subjects without active TB disease.

Outcome measures

Outcome measures
Measure	Placebo n=325 Participants	MVA85A/AERAS-485 n=324 Participants
Percentage of Participants With Adverse Events	96.0 percentage of participants with an AE	99.1 percentage of participants with an AE

SECONDARY outcome

Timeframe: For at least 6 months post second vaccination up to 33 months total follow-up.

Population: Per protocol: All randomized subjects who received a dose of study vaccine and had no major protocol deviations, were still ongoing in the study 28 days after Study Day 0, and did not have TB diagnosed within 28 days after Study Day 0.

Efficacy of MVA85A/AERAS-485 in the prevention of TB disease compared to control subjects who received placebo in HIV-infected, African adult subjects without active TB disease.

Outcome measures

Outcome measures
Measure	Placebo n=325 Participants	MVA85A/AERAS-485 n=320 Participants
Number of TB Cases	9 participants with TB	6 participants with TB

SECONDARY outcome

Timeframe: Up to 6 months post second vaccination.

Population: Safety: All randomized ART negative subjects who received a dose of study vaccine, based on actual treatment received.

Outcome measures

Outcome measures
Measure	Placebo n=69 Participants	MVA85A/AERAS-485 n=67 Participants
CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in Anti-retroviral Therapy Negative (ART -)Subjects Study Visit 8	557.39 cells/mm^3 Standard Deviation 1.395	484.64 cells/mm^3 Standard Deviation 1.430
CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in Anti-retroviral Therapy Negative (ART -)Subjects Baseline	540.60 cells/mm^3 Standard Deviation 1.333	541.10 cells/mm^3 Standard Deviation 1.394

SECONDARY outcome

Timeframe: Up to 6 months post second vaccination.

Population: Safety: All randomized ART positive subjects who received a dose of study vaccine, based on actual treatment received.

Outcome measures

Outcome measures
Measure	Placebo n=256 Participants	MVA85A/AERAS-485 n=257 Participants
CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Subjects Baseline	568.07 cells/mm^3 Standard Deviation 1.387	564.27 cells/mm^3 Standard Deviation 1.395
CD4+ Lymphocyte Counts Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Subjects Study Visit 8	606.07 cells/mm^3 Standard Deviation 1.430	604.24 cells/mm^3 Standard Deviation 1.449

SECONDARY outcome

Timeframe: Up to 6 months post second vaccination.

Population: Safety: All randomized ART - subjects who received a dose of study vaccine, based on actual treatment received.

Outcome measures

Outcome measures
Measure	Placebo n=68 Participants	MVA85A/AERAS-485 n=65 Participants
HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART - Participants Baseline	6918.76 copies/mL Standard Deviation 8.673	9616.55 copies/mL Standard Deviation 9.783
HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART - Participants Study Visit 8	9090.32 copies/mL Standard Deviation 14.101	6437.59 copies/mL Standard Deviation 25.781

SECONDARY outcome

Timeframe: Up tp 6 months post second vaccination

Population: Safety: All randomized ART + subjects who received a dose of study vaccine, based on actual treatment received.

Outcome measures

Outcome measures
Measure	Placebo n=249 Participants	MVA85A/AERAS-485 n=253 Participants
HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Participants. Baseline	26.32 copies/mL Standard Deviation 1.339	26.87 copies/mL Standard Deviation 1.500
HIV-1 Viral Load Before and After Administration of MVA85A/AERAS-485 Compared to Placebo in ART+ Participants. Study visit 8	27.30 copies/mL Standard Deviation 1.580	29.39 copies/mL Standard Deviation 2.040

SECONDARY outcome

Timeframe: 28 days post second vaccination.

Population: First 70 patients enrolled who also had pre-vaccination results available were analyzed.

Immunogenicity of MVA85A/AERAS-485 compared to placebo as described by the ex vivo interferon (IFN)-γ enzyme linked immunospot (ELISpot).

Outcome measures

Outcome measures
Measure	Placebo n=33 Participants	MVA85A/AERAS-485 n=31 Participants
Counts of Spot-forming Units After Stimulation With AG85A Peptide Pool.	9.00 SFU - background/10^6 PBMC Interval 4.0 to 30.0	254.00 SFU - background/10^6 PBMC Interval 92.0 to 462.0

SECONDARY outcome

Timeframe: 7 days post second vaccination.

Population: First 70 patients enrolled who also had pre-vaccination results available were analyzed.

The antigen-specific negative control-subtracted response for any cytokine (Interferon gamma \[INFγ\] , Interleukin 2 \[IL2\], Interleukin 17 \[IL17\] and tumor necrosis factor \[TNF\]).

Outcome measures

Outcome measures
Measure	Placebo n=32 Participants	MVA85A/AERAS-485 n=31 Participants
Immunogenicity of MVA85A/AERAS-485 Compared to Placebo as Described by Flow Cytometric Intracellular Cytokine Staining (ICS) of CD4+ and CD8+ T Cells After Stimulation With a Peptide Pool of Mycobacterial Antigens. CD4+	0.14 Percent responding TCells Interval 0.1 to 0.16	0.20 Percent responding TCells Interval 0.16 to 0.34
Immunogenicity of MVA85A/AERAS-485 Compared to Placebo as Described by Flow Cytometric Intracellular Cytokine Staining (ICS) of CD4+ and CD8+ T Cells After Stimulation With a Peptide Pool of Mycobacterial Antigens. CD8+	0.00 Percent responding TCells Interval 0.0 to 0.02	0.04 Percent responding TCells Interval 0.01 to 0.04

SECONDARY outcome

Timeframe: For at least 6 months post second vaccination up to 33 months total follow-up.

Outcome measures

Outcome measures
Measure	Placebo n=173 Participants	MVA85A/AERAS-485 n=186 Participants
QuantiFERON (QFN) Conversion Rate in MVA85A/AERAS-485 Recipients Compared to Control Subjects Without a Diagnosis of Tuberculosis During the Trial.	40 participants who converted	38 participants who converted

Adverse Events

Placebo

Serious events: 17 serious events

Other events: 310 other events

Deaths: 0 deaths

MVA85A/AERAS-485

Serious events: 17 serious events

Other events: 320 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Product Director; Bernard Landry

Aeras

Phone: 301-547-2919

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo n=325 participants at risk	MVA85A/AERAS-485 n=324 participants at risk
Infections and infestations Bronchopneumonia	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Erysipelas	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Eye infection syphilitic	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Localised infection	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Malaria	0.62% 2/325 • Number of events 3 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Meningitis tuberculous	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Meningitis viral	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Pneumonia	0.62% 2/325 • Number of events 2 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Pulmonary tuberculosis	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Infections and infestations Septic shock	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Psychiatric disorders Anxiety disorder	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Psychiatric disorders Suicide attempt	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Nervous system disorders Convulsion	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Nervous system disorders Hemiplegia	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Nervous system disorders Meningorrhagia	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Nervous system disorders Transient ischaemic attack	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Nervous system disorders VIIth nerve paralysis	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Cardiac disorders Atrioventricular block complete	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Vascular disorders Deep vein thrombosis	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Gastrointestinal disorders Gastritis	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Gastrointestinal disorders Haematemesis	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.39% 1/255 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	1.1% 3/265 • Number of events 3 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Pregnancy, puerperium and perinatal conditions Intra-uterine death	0.00% 0/255 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.38% 1/265 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Congenital, familial and genetic disorders Congenital anomaly	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.31% 1/324 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Death	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/324 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Death neonatal	0.39% 1/255 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	0.00% 0/265 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.

Measure	Placebo n=325 participants at risk	MVA85A/AERAS-485 n=324 participants at risk
Blood and lymphatic system disorders Anaemia	13.8% 45/325 • Number of events 51 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	12.3% 40/324 • Number of events 41 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Blood and lymphatic system disorders Leukopenia	14.8% 48/325 • Number of events 52 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	13.6% 44/324 • Number of events 49 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Blood and lymphatic system disorders Neutropenia	37.5% 122/325 • Number of events 139 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	39.5% 128/324 • Number of events 157 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Nervous system disorders Headache	28.0% 91/325 • Number of events 136 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	37.3% 121/324 • Number of events 177 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Cardiac disorders Tachycardia	4.6% 15/325 • Number of events 16 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	6.2% 20/324 • Number of events 21 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Vascular disorders Diastolic hypertension	15.7% 51/325 • Number of events 61 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	17.3% 56/324 • Number of events 65 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Vascular disorders Systolic hypertension	9.2% 30/325 • Number of events 40 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	13.9% 45/324 • Number of events 51 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Respiratory, thoracic and mediastinal disorders Tachypnoea	16.0% 52/325 • Number of events 58 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	15.1% 49/324 • Number of events 57 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Gastrointestinal disorders Nausea	11.4% 37/325 • Number of events 45 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	11.4% 37/324 • Number of events 43 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Musculoskeletal and connective tissue disorders Arthralgia	16.3% 53/325 • Number of events 70 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	26.2% 85/324 • Number of events 111 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Musculoskeletal and connective tissue disorders Myalgia	20.9% 68/325 • Number of events 89 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	39.2% 127/324 • Number of events 174 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Fatigue	21.5% 70/325 • Number of events 94 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	36.4% 118/324 • Number of events 146 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site discharge	0.31% 1/325 • Number of events 1 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	6.8% 22/324 • Number of events 23 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site erythema	2.5% 8/325 • Number of events 8 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	13.0% 42/324 • Number of events 46 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site exfoliation	34.2% 111/325 • Number of events 145 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	75.0% 243/324 • Number of events 364 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site pain	29.2% 95/325 • Number of events 128 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	70.7% 229/324 • Number of events 370 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site pruritus	49.5% 161/325 • Number of events 247 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	75.0% 243/324 • Number of events 420 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site swelling	3.4% 11/325 • Number of events 13 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	18.2% 59/324 • Number of events 74 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site ulcer	1.8% 6/325 • Number of events 6 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	32.7% 106/324 • Number of events 130 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site vesicles	0.00% 0/325 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	6.8% 22/324 • Number of events 22 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Injection site warmth	33.2% 108/325 • Number of events 145 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	55.6% 180/324 • Number of events 271 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
General disorders Malaise	18.2% 59/325 • Number of events 77 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	35.5% 115/324 • Number of events 143 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Investigations Alanine aminotransferase increased	12.0% 39/325 • Number of events 41 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	11.1% 36/324 • Number of events 39 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Investigations Aspartate aminotransferase increased	10.5% 34/325 • Number of events 37 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	9.9% 32/324 • Number of events 33 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Investigations Blood alkaline phosphatase increased	12.0% 39/325 • Number of events 40 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	10.2% 33/324 • Number of events 38 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Investigations Gamma-glutamyltransferase increased	14.2% 46/325 • Number of events 48 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	14.8% 48/324 • Number of events 53 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Investigations Haemoglobin decreased	8.6% 28/325 • Number of events 31 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	7.4% 24/324 • Number of events 24 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.
Investigations Neutrophil count decreased	6.8% 22/325 • Number of events 25 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.	9.6% 31/324 • Number of events 36 • AEs reported 28 after each vaccine. SAEs reported for the duration of the study; for at least 6 months after last vaccine up to 33 months total follow-up.