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`EXHIBIT 3
`EXHIBIT 3
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`

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`Vaccine 37 (2019) 3326-3334
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`Contents lists available at ScienceDirect
`
`=
`
`\Vaccine
`
`
`
`“t,t
`
`ELSEVIER
`
`journal homepage: www.elsevier.com/locate/vaccine
`
`Vaccine
`
`
`
`mRNAvaccines against H10N8 and H7N9influenza viruses of pandemic ®
`potential are immunogenic and well tolerated in healthy adults in phase|Ss"
`1 randomizedclinical trials
`
`Robert A. Feldman *', Rainard Fuhr”:', Igor Smolenov‘, Amilcar (Mick) Ribeiro‘, Lori Panther‘,
`Mike Watson“, Joseph J. Senn‘, Mike Smith‘, Orn Almarsson ‘, Hari S. Pujar‘, Michael E. Laska‘,
`James Thompson‘, Tal Zaks‘, Giuseppe Ciaramella ©
`* Miami Research Associates, 6280 Sunset Drive, Suite 600, So. Miami, FL 33143, USA
`> PAREXEL International GmbH Klinikum Westend, House 18, Spandauer Damm 130, 14050Berlin, Germany
`© Moderna, 500 Technology Square, Cambridge, MA 02139, USA
`
`ARTICLE INFO
`
`ABSTRACT
`
`Article history:
`Received 8 November 2018
`Received in revised form 16 April 2019
`Accepted 24 April 2019
`Available online 10 May 2019
`
`—
`Sisrctiiaay
`Panenic within
`Safety
`Immunogenicity
`
`Background: We evaluated safety and immunogenicity of the first mRNA vaccines against potentially
`pandemic avian H10N8 and H7N9influenza viruses.
`Methods: Two randomized, placebo controlled, double blind, phase 1 clinical trials enrolled participants
`between December 2015 and August 2017 at single centers in Germany (H10N8) and USA (H7N9).
`Healthy adults (ages 18 64 years for HION8 study; 18 49 years for H7N9 study) participated.
`Participants received vaccine or placebo in a 2 dose vaccination series 3 weeks apart. H10N8 intramus
`cular (IM) dose levels of 25, 50, 75, 100, and 400 pg andintradermal dose levels of 25 and 50 pg were
`evaluated. H7N9 IM 10 , 25, and 50 pg dose levels were evaluated; 2 dose series 6 months apart was
`also evaluated. Primary endpoints were safety (adverse events) and tolerability. Secondary immuno
`genicity outcomes included humoral (hemagglutination inhibition [HAI], microneutralization [MN]
`assays) and cell mediated responses (ELISPOT assay).
`Results: H10N8 and H7N9 mRNA IM vaccines demonstrated favorable safety and reactogenicity profiles.
`Novaccine related serious adverse event was reported. For HION8 (N 201), 100 pg IM dose induced
`HAI titers > 1:40 in 100% and MN titers > 1:20 in 87.0% of participants. The 25 yg intradermal dose
`induced HAItiters > 1:40 in 64.7% of participants compared to 34.5% ofparticipants receiving the IM dose.
`For H7N9(N_
`156), IM dosesof 10, 25, and 50 pg achieved HAI titers > 1:40 in 36.0%, 96.3%, and 89.7% of
`participants, respectively. MNtiters > 1:20 were achieved by 100%inthe 10 and 25 pg groups and 96.6%
`in the 50 pg group. Seroconversion rates were 78.3% (HAI) and 87.0% (MN) for H10N8 (100 pg IM) and
`96.3% (HAI) and 100% (MN) in H7N9 (50 pg). Significant cell mediated responses were not detected in
`either study.
`Conclusions: The first mRNA vaccines against H1ON8 and H7N9influenza viruses were well tolerated and
`elicited robust humoral immuneresponses.
`ClinicalTrials.gov NCT03076385 and NCT03345043.
`© 2019 The Author(s). Published by Elsevier Ltd. This is an open accessarticle under the CC BY NC ND
`license (http://creativecommons.org/licenses/by nc nd/4.0/).
`
`1. Introduction
`
`* Corresponding author at: Moderna, 500 Technology Square, Cambridge, MA
`02139, USA.
`E-mail addresses; Rainard.Fuhr@parexel.com (R. Fuhr), Lori.Panther®modermatx.
`com (L. Panther), mike.watson@modernatx.com (M. Watson), Joe.senn@modernatx.
`com (JJ. Senn), Mike.smith@modernatx.com (M.Smith), Orn.almarsson@®modematx.
`com (6. Almarsson), Hari.pujar®modernatxcom (HS. Pujar), James.thompson@
`modernatx.com (J. Thompson), Tal.zaks@modernatx.com (T. Zaks).
`' These authors contributed equally to this manuscript.
`
`H10N8avian influenza first breached the avian humanspecies
`barrier in 2013, and was fatal in 2 of the 3 three persons infected
`{1]. No additional H1ON8 human infections have been reported,
`but the virus has a high affinity for the human receptor, and
`mutated strains with increased virulence are a significant concern
`{2]. Also in 2013, the first human H7N$9infections were reported in
`China, with a fatality rate of 37% [3]. Since 2013, five waves of
`H7N9 outbreaks have caused over 1500 documented infections
`
`https://doi.org/10.1016/j.vaccine.2019.04.074
`0264-410X/© 2019 The Author(s). Published by Elsevier Ltd.
`This is an open access article under the CC BY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).
`
`

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`and more than 600 deaths [4]. In February 2017, the pandemic
`threat was further highlighted by a death due to a highly patho
`genic H7N9 strain with a R292K amino acid mutation associated
`with neuraminidase inhibitor resistance [5].
`Emerging influenza strains reinforce the urgent need for vaccine
`technologies with precise yet flexible antigen design that generate
`potent and well tolerated immuneresponseswith rapidly scalable,
`high volume manufacturing [6]. Egg based technologies do not
`fulfil
`these requirements. During the 2009 H1N1 pandemic,
`6 monthselapsed from thestart of the epidemic until the first vac
`cine doses became available, and an additional 2 months were
`needed to producethe tens of millions of doses required for the
`epidemic [6]. The vaccine itself was effective [7,3], suggesting that
`earlier deployment could have had greater impact. Stockpiling
`strategies are expensive and lack the flexibility to continuously
`adapt the vaccine to mutating threats [9]. For example, currently
`stockpiled vaccines against H7N9 are expected to offer reduced
`protection against the emerging “wave five” Yangtze River Delta
`Lineage virus [10].
`MRNAvaccines havethe potential for rapid, high volume man
`ufacturing with the precision andflexibility of antigen design nec
`essary to provide both timely and effective responses to emerging
`threats from influenza and other pathogens. They also offer the
`opportunity for a more flexible stockpiling approach, with the
`potential to store low volumelibraries of frozen plasmid and/or
`unformulated mRNA for many decades, which can be rapidly for
`mulated and distributed as threat levels rise. mRNA vaccines can
`direct expression of virtually any membrane bound, soluble, or
`polyprotein antigens, mimicking antigen expression during natural
`infection [11]. For influenza, mRNAvaccines could also avoid anti
`genic drift associated with egg based vaccine production [12].
`Additional advantages are economies in time, cost, and scale that
`derive from using a single development and manufacturing plat
`form. Production of mRNA vaccines does not require pathogen
`growth: only identification, optimization, and mRNA expression
`of protective antigen(s) are required.
`To assess the safety and immunogenicity of mRNA influenza
`vaccines, we have developed two avian influenza strains of pan
`demic potential [13] in our lipid nanoparticle (LNP) formulated
`mRNAvaccine platform. We present safety and immunogenicity
`data from two phase 1,
`randomized, double blind, placebo
`controlled studies of HiON8 and H7N9 mRNAvaccinesin healthy
`adults, The tolerability and immunogenicity of different dose levels
`and routes of administration were explored.
`
`2. Methods
`
`2.1. Study design and participants
`
`Two phase 1, randomized, double blind, placebo controlled,
`dose ranging studies evaluated mRNA H1ON8 and mRNA H7N9
`vaccines at single centers in Berlin, Germany (PAREXEL Interna
`tional) and South Miami, Florida, USA (Miami ResearchAssociates),
`respectively. Eligible participants were healthy adults who pro
`vided written consent and had noprior history of adverse reactions
`to influenza vaccinations, diagnosis of Guillain Barré syndrome,
`receipt of licensed vaccines within 2 4 weeks, receipt of H10N8
`or H7N9 vaccine at any time, or history of poultry or wild bird
`handling.
`In the H10N8 study, participants aged 18 64 years were ran
`domized to receive two doses of vaccine or placebo 3 weeks apart
`at intramuscular (IM) doselevels of 25, 50, 75, 100, and 400 pg or
`intradermal (ID) dose levels of 25 and 50 pg. In the H7N9study,
`adults aged 18 49 years received two dosesof vaccine or placebo
`3 weeks apart at IM dose levels of 10, 25, and 50 yg. A protocol
`
`amendment allowed participants in the 25 and 50yg IM dose
`groupsto receive a booster dose at 6 months,
`The H10N8trial was approved by the Ethics Committee of the
`Land Berlin, State Office for Health and Social Affairs, Berlin, Ger
`many. The H7N9trial was approved by the Chesapeake Interna
`tional Review Board, Columbia, Maryland. The studies were
`designed in accordance with the Guidance on Clinical Evaluation
`of New Vaccines [14] and were conducted in compliance with
`the International Conference on Harmonization Good Clinical Prac
`tice guidelines and theethical principles of the Declaration of Hel
`sinki. All participants provided written, informed consent before
`initiation of any study related procedures.
`
`2.2, Vaccines
`
`The H10N8 and H7N9 mRNAvaccines consisted of chemically
`modified mRNAs encoding the full length, membrane bound form
`of the hemagglutinin (HA) glycoprotein from the H10N8 influenza
`strain (A/Jiangxi Donghu/346/2013) or the H7N9 influenza strain
`(A/Anhui/1/2013). An LNP delivery system was used as previously
`described [15]. The H10N8 and H7N9 vaccines were manufactured
`in compliance with current Good Manufacturing Processes. Each
`vaccine vial contained 2 mg/mL H10N8 or H7N9 mRNA and
`40 mg/mL of LNP excipients formulated in isotonic 8.0% sucro
`se/20 mM buffer. Study vaccine wasdiluted with 0.9% saline and
`administered at a final injection volume of 200 pL. Placebo doses
`were200 pL of 0.9% sodium chloride. The initial vaccine doses were
`selected according to the Guidance for Industry based on the pre
`clinical animal models [13,16].
`
`2.3. Procedures
`
`All participants and study personnel responsible for any clinical
`evaluations were masked to treatment arm assignment except for
`3 sentinel participants in each dose group receiving active vaccine.
`Vaccines were prepared and administered by unmasked study per
`sonnel with no other study involvement. A third party biostatisti
`cian performed interim analyses. Randomization codes were
`generated centrally and stored at study sites with accessrestricted
`to designated personnel.
`At each doselevel, 3 sentinel participants receiving active vac
`cine were sequentially enrolled 48h apart for safety evaluation.
`After review of safety data through 14 daysafter last sentinel vac
`cination, additional participants were randomized 3:1 to vaccine or
`placebo, The study advanced similarly for each subsequent dose
`level. No sentinel participants were enrolled in the H10N8 vaccine
`50 and 75 ug IM dosegroups as they were addedafter enrollment
`of the 100 ug dose group. IM doses were delivered in the deltoid
`following standard procedures; ID doses were delivered over the
`deltoid area. All H7N9 vaccines were administered IM in the del
`toid muscle.
`
`2.4, Safety monitoring
`
`In both studies, physical examinations,vital signs, and clinical
`laboratory assessments were conducted at screening and at days
`1 (prior to first vaccination), 8, 22 (prior to second vaccination),
`30, and 43. Participants were observed for 60 min after vaccination
`and followed for 1 year after last vaccination. Safety blood testing
`was performed at specific timepoints through 21 days after each
`vaccination (eAppendix 1), Participant diary cards captured soli
`cited local adverse events (AEs; injection site pain, tenderness, ery
`thema, ecchymosis, and injection site swelling) and solicited
`systemic AEs
`(headache,
`fatigue, myalgia, arthralgia, nausea,
`vomiting, diarrhea,chills, loss of appetite, malaise, and fever) from
`the day of each vaccination through the following 6 days, and
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`and SAEs. Secondary immunogenicity endpoints were HAI (per
`unsolicited AEs through 21 days after each vaccination. Partici
`centageof participants with HAItiters > 1:40) and MN(percentage
`pants wereinstructed to call or return to the study site within
`of participants with MN titers > 1:20) seroprotective rates and
`24 hif any AE wassevereorlife threatening during thefirst 7 days
`seroconversion rates at day 43. HAI seroconversion rates were
`following vaccination.
`defined as baseline HAI
`titer<1:10 and post vaccination
`The intensity of AEs and laboratory abnormalities was graded
`titer > 1:40 or baseline titer > 1:10 and > 4 fold increase in post
`by the investigator as mild (Grade 1), moderate (Grade 2), severe
`vaccination titer. MN seroconversion rates were defined as base
`(Grade 3), or potentially life threatening (Grade 4) using the Center
`for Biologics Evaluation and Research toxicity grading scale [17].
`line MN titer < 1:10 and post vaccination titer > 1:20 or baseline
`
`AEs were determined by the investigator to be probably, possibly, titer > 1:10 and >4fold increase in post vaccination titer. HAI
`or not related to study vaccine. Serious AEs (SAEs), severe AEs,
`and MNantibody responses were described as the anti log of the
`medically attended AEs, events of special interest (AESI; a subset
`arithmetic mean of the log 10 transformed titers (GMTs) and geo
`of potentially immune mediated medical conditions that are his
`metric mean ratios (GMR, post vaccination titer to baselinetiter).
`torically associated with a vaccination), new onset of chronic ill
`Endpoints were defined according to the international guidelines
`ness, and AEs
`leading to study withdrawal were collected
`for vaccine evaluation [20].
`throughout each study. All AEs were monitored until resolution,
`or if the event becamechronic, until a cause was identified.
`For each study, an independent safety monitoring committee
`performeda blinded safety data review at pre specified time points
`prior to proceeding to the next dose level. Rules to pause the study
`werein place to halt further dosing until a safety review was per
`formed (eAppendix 1). For the H10N8 study, the study was paused
`for any vaccine related anaphylactic reaction, generalized urticarial
`event, severe unsolicited systemic event, or any SAE. In addition,for
`any H10N8 cohort (with or withoutsentinel), the study was paused
`for any severesolicited AE (systemic or local), any Grade 4 vaccine
`related AE, or 3 or more Grade 3 vaccine related AEs in any one
`treatment arm. For the H7N9study, the study was paused for any
`vaccine related systemic hypersensitivity event, severe solicited
`AE (systemic or local), severe unsolicited AE, SAE, Grade 4 AE, or 3
`or more severe AEs in any one treatment arm.
`
`2.7. Statistical analysis
`
`Descriptive statistics were used to summarize demographic and
`baseline characteristics; there was no planned formalstatistical
`testing. Sample size was not hypothesis driven. A sample size of
`30 participants per dose level was planned in both studies; how
`ever, actual enrollment was determined by safety and reactogenic
`ity data at each of the doselevels.
`Safety and immunogenicity data were analyzed using summary
`Statistics,
`and
`included
`all
`randomized participants who
`received > 1 dose of vaccine or placebo. Solicited and unsolicited
`AEs and SAEs were reported as numbers and percentages. AEs were
`coded using Medical Dictionary for Regulatory Activities (MedDRA)
`preferred terms.
`Day 43 analyses of HAI and MN GMT, GMR, seroconversion, and
`antibody response were conducted for participants who received
`both doses of vaccine and provided immunogenicity data at base
`line and day 43. GMR wascalculated as the ratio of GMT pre
`vaccination (day 1) to GMT at day 43. The fold increase in titer
`wascalculated as a ratio of GMT at Day 43 (21 days after the sec
`ond vaccination) to the pre vaccination GMT on Day 1 for each par
`ticipant with both Day 1 and Day 43 results. For GMT calculations,
`values that were reported as below the lowerlimit of quantitation
`(LLOQ) were replaced by 0.5 x LLOQ, For calculations of fold rise,
`values < LLOQ were replaced by 0.5 x LLOQ for the numerator
`and by LLOQ for the denominator.
`Antibody persistence analyses included all participants who
`received > 1 dose and provided immunogenicity data at day 22,
`andall participants who received both doses of vaccine and pro
`vided immunogenicity data at any or all days 43, 84, or 183
`(H10N8 study), and days 43, 84, or 205 (H7N9 study). HAI and
`MN GMTsandtheir associated 95% confidence intervals (CIs) were
`reported by study and doselevel. Continuous variables were calcu
`lated as means with 95% CIs or means with standard deviations
`(SD). Statistical analyses were performed using SAS® version 9.1
`or higher (SAS Institute Inc., Cary, North Carolina, United States).
`
`3. Results
`
`3.1. Participants
`
`Participants were enrolled in the H1ON8 study from December
`2015 to December 2016 and in the H7N9 study from February
`2016 to February 2017. There were 201 participants randomized
`in the H10N8study; 145 received IM vaccination and 56 received
`ID vaccination (Fig. 1). In the IM dose groups, 144 participants
`received the first vaccination and provided immunogenicity sam
`ples at day 22, and 107 participants received both vaccinations
`and provided immunogenicity samples at baseline and day 43.
`The second vaccination in the 75 pg dose group was notinitiated
`
`2.5. Immunogenicity assessments
`
`Immunogenicity was determined by hemagglutination inhibi
`tion (HAI) using recombinant, full length HA proteins for H10N8
`(Ajjiangxi Donghu/346/2013, Medigen)
`or
`the A/Shang
`hai/O2/2013XPR8 virus for H7N9 and by microneutralization
`(MN)assays, using the A/quail/Italy/1117/1965 and the A/Shang
`hai/O2/2013XPR8 viruses for H1ON8 and H7NQ,respectively, as
`previously described [18,19]. Testing for HAI was performed on
`blood samplescollected at days 1, 8, 22, 30, 43, and 84, and testing
`for microneutralization (MN) assays was performed on blood sam
`ples collected at days 1, 22, and 43. Blood samples for HAI persis
`tence testing were collected at approximately 6 and 12 months
`after the last vaccination. Peripheral blood mononuclear cells
`(PBMC) werecollected at days 1, 6, 22, 30, 43, and 84 and were
`analyzed by enzymelinked immunospot (ELISPOT).
`Serum antibodies to influenza virus HA proteins (HAI assay)
`were measured by serial dilution of heat inactivated sera incu
`bated with the titer reported as the reciprocal of the highest dilu
`tion that effectively inhibited agglutination of red blood cells by a
`specific influenza strain. Serum neutralizing antibodies (MN assay)
`were measured byserial dilution of heat inactivated sera incu
`bated with influenza virus and transferred to plates containing
`Madin Darby canine kidney (MDCK) cells, with the titer reported
`as the reciprocal of the highest dilution at which no cytopathic
`effect was observed. Influenza viruses A/quail/Italy/1117/1965
`and A/Shanghai/02/2013XPR8 were used for H1ON8 and H7N9
`MNassays, respectively [18,19]. Cell mediated immune response
`wasassessed by interferon y ELISPOT assays of PBMC stimulated
`with H10N8 and N7N9 HA protein peptide libraries.
`
`2.6. Outcomes
`
`The primary endpoints were safety and reactogenicity as mea
`sured by frequency and severity of solicited AEs, unsolicited AEs,
`
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`3329
`
`H10N8
`Participants enrolled
`N=201
`
`
`IM administration
`N=145
`
`ID administration
`N=56
`
`
`
`
`
`
`
`
`
`
`Placebo
`Placebo
`
`
`50 yg IM
`100 pg IM
`400 pg IM
`n=30
`n=23
`n=3
`n=35
`n=13
`
`
`
`Withdrawal
`Withdrawal
`Withdrawal
`Withdrawal
`
`n=3
`n=2
`n=1
`n=1
`* Adverse
`«Adverse
`* Protocol
`*Protocol
`event”
`event?
`deviation
`deviation
`
`
`
`n=27
`Received
`Received
`Received
`Received
`Received
`
`
`
`
`Dose 2
`Dose 2
`Dose 2
`Dose 2
`Dose 2
`
`
`
`
`n=0
`n=29
`n=28
`n=23
`n=0
`
`
`
`
`
`IM dose groups:
`Dose 1 immunogenicity population N=144¢
`Dose 2 immunogenicity population N=107
`Safety population N=145
`
`Withdrawal
`n=1
`«Adverse
`event®
`
`Received
`Dose 2
`
`Received
`Received
`Received
`Dose 2
`Dose 2
`Dose 2
`n=0
`n=30
`n=9
`
`
`
`
`
`
`ID dose groups:
`Dose 1 immunogenicity population N=56
`Dose 2 immunogenicity population N=39
`Safety population N=56
`
`Placebo participants were pooled from all treatment armsof similar administration (IM or ID). Immunogenicity population was based on participants who provided evaluable blood
`samples.All enrolled participants received Dose 1. Dose 2 was administered 21 days after Dose 1. Participant withdrawals are those who withdrew by day 18. @Events included
`severe fatigue on day of vaccination (n=1) and severe erythema on dayof vaccination (n=1). Events includedinjection site erythema on dayof vaccination (n=1), severe
`headache2 daysafter vaccination (n=1), and other (n=1). ‘Event was a moderate cold 3 daysafter vaccination (n=1). “1 participant did not provide an evaluable blood sampleat
`day 22.
`
`Fig. 1. Patient flow for the H10N8 Study.
`
`after finding minimal safety concerns in the previously completed
`100 yg dose group. Baseline characteristics were similar across all
`IM dose groups (Table 1). Of the 56 participants in the ID dose
`groups whoreceived thefirst vaccination, 39 received the second
`vaccination. In the 50 yg ID dose group, enrollment was halted
`because of local reactogenicity, and the second vaccination was
`not administered. Baseline characteristics for the ID dose groups
`are shownin eTable 1 (supplemental materials).
`There were 156 participants randomized in the H7N9 study
`(Fig. 2). Thirty participants in the day 1 and day 21 dose groups
`at the 10 , 25 , and 50 yg dose levels received both vaccinations.
`Overall, 122 participants provided immunogenicity data at 21 days
`after the first dose, and 117 participants received 2 doses, provided
`samples at day 43, and were included in day 43 immunogenicity
`evaluations. Baseline characteristics were similar across all dose
`groups (Table 1). Ten participants in the day 1, month 6 dose
`groups received the first vaccination, and 3, 0, and 2 participants
`received the second vaccination at the 10 , 25 , and 50 pg dose
`levels, respectively.
`
`ing dose for both first and second vaccinations. In the 400 pg IM
`dose group, 2 sentinel participants experienced grade 3 solicited
`AEs (1 injection site erythema, 1 headache) within 24 h ofthefirst
`vaccination, which resolved spontaneously but met study pause
`rules (data not shown). After safety review, further 400 pg IM vac
`cinations were stopped. In the 75 pg IM dosegroup, 2 participants
`experienced grade 3 solicited AEs (1 severe swelling, 1 with severe
`fatigue, myalgia, and injection site pain) following the first vacci
`nation (data not shown).
`Overall, 124 unsolicited AEs were reported in the IM dose
`groups. The most commonunsolicited AEs were upper respiratory
`tract infection, back pain, pharyngitis, and oropharyngeal pain.
`Three severe unsolicited AEs (back pain, tonsillitis, ruptured ovar
`ian cyst) and 2 SAEs (cholecystitis, ruptured ovarian cyst) were
`reported and deemed unrelated to vaccination. No AESIs or cases
`of new onsetof chronic illness were reported.
`ID vaccination was associated with high rates of solicited AEs
`(eTable 2, supplemental materials), and the sponsorelected to dis
`continue enrollmentof these cohorts.
`
`3.2. Safety
`
`3.2.1. HION8 study
`Solicited local and systemic AEs are summarized Table 2. In the
`IM dose groups,injection site pain after either dose was the most
`commonsolicited local AE (78.6 93.1%), followed by erythema
`(0 17.4%), and injection site swelling (6.7 16.7%). There were 3
`Grade 3 solicited local AEs, which all occurred in the 100 pg dose
`group. The most commonsolicited systemic AEs after either IM
`dose were myalgia (7.8 58.6%), fatigue (26.7 47.8%), and headache
`(14.3 69.6%). Mostsolicited systemic reactions were mild to mod
`erate in severity, of short duration (1 3 days), and resolved with
`out intervention. The incidence of fever was higher following the
`second dose in the 100 ug dose group and increased with increas
`
`3.2.2. H7N9 study
`For H7N9, injection site pain was the most commonsolicited
`local AE after either IM dose (43.3 80.0%), followed by swelling
`(16.7 30.0%) (Table 2); there was no injection site erythema above
`Grade 1. No severe local solicited AEs were reported afterfirst vac
`cination; however, 3 participants in the 50 pg dose group experi
`enced severe injection site pain after the second vaccination. The
`most commonsolicited systemic AEs after either dose were head
`ache
`(10.0 26.7%), myalgia
`(10.0 26.7%),
`and
`arthralgia
`(6.7 20.0%). Eleven of the 12 severe solicited AEs occurred in the
`50 yg dose group; nonerequired intervention or caused early ter
`mination. Except for fever in 50 pg dose group, the frequency of
`solicited local or systemic AEs did not increase after the second
`vaccination (Table 2).
`
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`Table 1
`Baseline characteristics of IM administration dose groups.
`
`H10NB8Study (IM administration)
`25 pg
`50 pg
`75 wg
`(n= 30)
`(n= 30)
`(n= 24)
`43.1
`42.8
`43.3
`Age, mean yrs
`(20-62)
`(21-61)
`(19-62)
`(range)
`17 (57)
`15 (50)
`10 (42)
`Sex, n male (%)
`29 (97)
`29 (97)
`23 (96)
`Race, n white (%)
`24.3
`25.5
`24.6
`BMI, mean kg/m?
`All subjects received vaccinations at day 1 and day 21.
`IM,intramuscular; BMI, body mass index.
`
`100 pg
`(n= 23)
`52.5
`(32-64)
`11 (48)
`21 (91)
`24.9
`
`400 pg
`(n=3)
`45.3
`(35-55)
`2 (67)
`3 (100)
`22.3
`
`Placebo
`(n= 35)
`41.4
`(35-55)
`22 (63)
`35 (100)
`24.7
`
`H7N8 Study (IM administration)
`10 ug
`25 wg
`50 pg
`(n= 30)
`(n= 30)
`(n= 30)
`35.3
`39.3
`34.6
`(20-49)
`(20-47)
`(19-47)
`18 (60)
`18 (60)
`15 (50)
`27 (90)
`19 (63)
`26 (87)
`24.9
`28.8
`27.3
`
`Placebo
`(n= 36)
`37.7
`(27-46)
`16 (44)
`30 (83)
`25.5
`
`
`H7N9
`Participants enrolled
`N=156
`
`
`
`
`10 yg IM
`n=40
`
`2-dose
`vaccination series
`n=30
`
`1-dose
`vaccination series
`n=10
`
`Received Dose 2
`(21 days)
`n=30
`
`Received Dose 2
`(6 months)
`n=3
`
`Withdrawal
`n=3
`+Other
`
`25 yg IM
`n=40
`
`50 pg IM
`n=40
`
`Placebo
`n=36
`
`2-dose
`1-dose
`2-dose
`vaccination series
`vaccination series
`vaccination series
`n=30
`n=10
`n=30
`
`v
`v
`v
`Received Dose 2
`Received Dose 2
`Received Dose 2
`(21 days)
`(6 months)
`(21 days)
`n=30
`n=2
`n=30
`v
`vw
`Withdrawal
`Withdrawal
`n=4
`n=1
`* Adverse event, n=1
`«Other
`
`1-dose
`vaccination series
`n=10
`
`Withdrawal
`
`n=2
`
`
`*Other
`
`
`
`
` +Other, n=3
`
`
`
`
`
`
`
`
`
`Safety population N=156
`
`H7N9 dose groups:
`Dose 1 immunogenicity population N=122
`Dose 2 (21 days) immunogenicity population N=117
`Dose 2 (6 months) immunogenicity population N=5
`
`Placeboparticipants were pooled from all treatment arms. Immunogenicity population was based onparticipants who provided evaluable blood samples. All enrolled participants received Dose
`1. Dose 2 was administered 21 days after Dose 1. Participant withdrawals are those who withdrew by day 18.
`
`Fig. 2. Patient flow for the H7N9 study.
`
`Percentages of participants who reported >1 unsolicited AE
`weresimilar across groups (53.3 73.3% vaccine; 63.9% placebo).
`Rates of severe unsolicited AEs were 0 20% vaccine and 8.3% pla
`cebo, The majority of possibly and probably related unsolicited
`AEs were > Grade 2 laboratory abnormalities and occurred at sim
`ilar rates in vaccine and placebo groups. Four severe unsolicited
`AEs were deemed possibly related to vaccination: 2 cases of
`increased alanine aminotransferase (1 50 pg, 1 placebo), 1 case of
`increased aspartate aminotransferase (50 ug), and 1 case of throm
`bocytopenia (placebo). All cases were asymptomatic and resolved
`without intervention. Five reported SAEs were deemed unrelated
`to vaccination: unintentional firearm related death, testicular can
`cer, pancreatitis, facial cellulitis, and exacerbated hypertension. No
`AESIs or cases of new onsetof chronic illness were reported.
`
`3.3. Immunogenicity
`
`For H10N8, HAI and MN GMT increased with increasing dose
`(Fig. 3A and B) and the percentage of participants with HAI
`titers > 1:40 or MN titers > 1:20 at day 43 also increased with
`increasing dose (Fig. 3C and D). At the 25 yg dose level, ID dosing
`induced higher HAI titers than IM dosing (eFigure 1, supplemental
`materials). In the H10N8 study, there was a discrepancy between
`
`the day 43 seroprotection rate and seroconversion rate in HAI at
`the 100 pg IM dose, and in MNat the 25 pg IM dose. The number
`of participants for each dose level was identical in the calculation
`of seroprotection rate and seroconversion rate. Of the 23 partici
`pants in the 100 pg dose group, 9 had baseline HAItiters < 1:10,
`10 had baseline HAI titers between >1:10 and <1:40, and 4 had
`baseline HAI titers > 1:40. Of the 30 participants in the 25 yg dose
`group, 25 had baseline MNtiters < 1:10, 1 had a baseline MNtiter
`between >1:10 and <1:20, and 4 had baseline MNtiters > 1:20. Six
`monthsafter the second 100 pg dose, HAI GMT was13.9 (Fig. 4A),
`and 22 of 23 participants (95.6%) remained seropositive (HAI
`titer > 1:10) (data not shown).
`For H7N9 participants dosed on days 1 and 22, post vaccination
`HAI and MN GMTsweregenerally high acrossall doses (Fig. 5A and
`B). The rate of HAI titer > 1:40 at day 43 was 96.3% in the 25 pg
`dose group (Fig. 5C). Across all dose levels, all but 1 participant
`achieved a post vaccination MN titer > 1:20 (Fig. 5D). Six months
`after vaccination, the HAI GMT was13.6 (Fig. 4B), and 13 of 25 par
`ticipants (52%) remained seropositive (HAI titer > 1:10; data not
`shown).
`Five participants (2 in the 25 yg dose level and 3 in the 10 pg
`dose level) received second doses at 6 months, HAI GMT increased
`from a baseline of 5 to 73 at the 10 pg dose, and 5 to 381 at the
`
`

`

`Case 1:22-cv-00252-MSG Document 193-3 Filed 01/16/24 Page 7 of 10 PageID #: 12555
`Case 1:22-cv-00252-MSG Document 193-3 Filed 01/16/24 Page 7 of 10 PagelD #: 12555
`
`RA. Feldman et al./ Vaccine 37 (2019) 3326-3334
`
`3331
`
`Table 2
`Solicited adverse events within 7 days after each IM vaccination on days 1 and 22.*
`
`Placebo
`n=36
`5 (13.9) [0]
`
`0 2
`
`(5.6) [0]
`6 (16.7) [0]
`2 (5.6) [0]
`6 (16.7) [0]
`4 (11.1) [0]
`1 (2.8) [0]
`
`0 n
`
`=36
`2 (5.6) [0]
`
`0 1
`
`(2.8) [0]
`1 (2.8) [0]
`
`oo
`
`ooco
`
`H7N9 Study (IM administration)
`10 pg
`25 pg
`50 pg
`n=30
`n=30
`n=30
`22 (73.3) [0]
`17 (56.7) [0]
`24 (80.0)[0]
`0
`0
`5(16.7)[0]
`5 (16.7) [0]
`5 (16.7) [0]
`5 (16.7) [0]
`1(3.3)[0]
`4. (13.3) [0]
`3 (10.0) [0]
`6 (20.0) [0]
`2(6.7)[0]
`3 (10.0) [0]
`1(3.3)[0]
`13.3)[0]
`0
`1 (3.3) [0]
`n=30
`n=30
`14 (46.7) [0]
`13 (43.3) [0]
`0
`0
`3(10.0)[0]
`6 (20.0) [0]
`3(10.0)[0]
` 2(6.7) [3.3]
`1(3.3)[0]
`3 10.0 [0]
`3 (10.0) [0]
`4 (13.3) [0]
`2(6.7)[0]
`1 (3.3) [0]
`0
`0
`0
`0
`
`=30
`22 (73.3) [10.0]
`
`0 6
`
`(20.0) [0]
`8 (26.7) [6.7]
`4 (13.3) [0]
`8 (26.7) [3.3]
`6 (20.0) [3.3]
`1 (3.3) [0]
`6 (20.0) [6.7]
`
`0 1
`
`0 (30.0)[0]
`7 (23.3) [6.7]
`3 (10.0) [0]
`8 (26.7) [0]
`3 (10.0) [0]
`1 (3.3) [0]
`
`0 n
`
`H10N8 Study (IM administration)
`25 pg
`50 pg
`n=30
`n=30
`23 (76.6) [0]
`25 (83.3) [0]
`1 (3.3) [0]
`2 (6.7) [0]
`5 (16.7) [0]
`8 (26.7) [0]
`16 (53.3) [0]
`0
`0
`1 (3.3) [0]
`n=28
`22 (78.6) [0]
`0
`2 (7.1) [0]
`4 (14.3) [0]
`8 (28.6) [0]
`14 (50.0) [0]
`0
`1 (3.6) [0]
`1 (3.6) [0]
`
`0 5
`
`(16.7) [0]
`12 (40.0) [0]
`13 (43.3) [0]
`17 (56.7) [0]
`2 (6.7) [0]
`1 (3.3) [0]
`1 (3.3) [0]
`n=29
`27 (93.1) [0]
`
`0 4
`
`(13.8) [0]
`14 (48.3)[0]
`13 (44.8)[0]
`17 (58.6)[0]
`2 (6.9) [0]
`1 (3.4)[0]
`2 (6.9) [0]
`
`Placebo
`n=35
`2 (5.7) [0]
`
`00 5
`
`(14.3) [0]
`7 (20.0)[0]
`1 (2.9)[0]
`1 (2.9) [0]
`
`00 n
`
`=27
`3 (11.1) [0]
`
`00 6
`
`(22.2)[3.7]
`4 (14.8)[0]
`1 (3.7) [0]
`1 (3.7) [0]
`
`(3.7) [0]
`
`0 1
`
`100 pg
`n=23
`19 (82.6)[0]
`3 (13.0) [0]
`3 (13.0) [0]
`7 (30.4)[0]
`8 (34.8) [0]
`12 (52.2) [0]
`2 (8.7) [0]
`1 (4.3) [0]
`2 (8.7) [0]
`n=23
`20 (87.0) [0]
`4 (17.4)[8.7]
`3 (13.0) [4.3]
`16 (69.6) [0]
`11 (47.8) [0]
`11 (47.8) [0]
`7 (30.4)[0]
`3 (13.0) [0]
`4 (17.4)[0]
`
`75 pg?
`n=24
`21 (87.5) [4.2]
`1 (3.3) [0]
`5 (16.7) [4.2]
`9 (37.5) [0]
`14 (58.3) [4.2]
`17 (70.9) [4.2]
`4 (16.7) [0]
`5 (20.8) [0]
`0
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`
`Dose 1
`Injection site pain
`Erythema
`Injection site swelling
`Headache
`Fatigue
`Myalgia
`Arthralgia
`Nausea
`Fever
`Dose 2
`Injection site pain
`Erythema
`Injection site swelling
`H