An influenza hemagglutinin stem nanoparticle vaccine induces cross-group 1 neutralizing antibodies in healthy adults
Authors: Widge Alicia T. , Hofstetter Amelia R. , Houser Katherine V. , Awan Seemal F. , Chen Grace L. , Burgos Florez Maria C. , Berkowitz Nina M. , Mendoza Floreliz , Hendel Cynthia S. , Holman LaSonji A. , Gordon Ingelise J. , Apte Preeti , Liang C. Jason , Gaudinski Martin R. , Coates Emily E. , Strom Larisa , Wycuff Diane , Vazquez Sandra , Stein Judy A. , Gall Jason G. , Adams William C. , Carlton Kevin , Gillespie Rebecca A. , Creanga Adrian , Crank Michelle C. , Andrews Sarah F. , Castro Mike , Serebryannyy Leonid A. , Narpala Sandeep R. , Hatcher Christian , Lin Bob C. , O’Connell Sarah , Freyn Alec W. , Rosado Victoria C. , Nachbagauer Raffael , Palese Peter , Kanekiyo Masaru , McDermott Adrian B. , Koup Richard A. , Dropulic Lesia K. , Graham Barney S. , Mascola John R. , Ledgerwood Julie E. ,   on behalf of the VRC 321 study team, Beck Allison , Casazza Joseph , Case Christopher L. , Misasi John , Ola Abidemi O. , Parker Karen , Wu Richard , Costner Pamela , Saunders Jamie , Novik Laura , Whalen William , Wang Xiaolin , Eshun Aba Mensima , Cunningham Jennifer , Arthur Anita , Anderson Morgan , Jones Justine , Larkin Brenda , Nguyen Thuy , Sitar Sandra , Le Lam , Pittman Iris , Vasilenko Olga , Yamshchikov Galina , Rothwell Ro Shauna , Burch Eugenia , Trofymenko Olga , Plummer Sarah , Evans Catina , Cartagena Cora Trelles , Hicks Renunda , Requilman LaShawn , Williams Pernell , Graves Carmencita , Telscher Shinyi , Albright Gabriela , Bahorich Jessica , Banappagari Sashikanth , Bender Michael , Caringal Alegria T. , Carvalho Juliane , Chaudhuri Rajoshi , Chintamani Mythili , Cooper Jonathan , Demirji Jacob , Dinh Tracey , Dobrescu Gelu , Goh Alvenne , Gollapudi Deepika , Gottumukkala Raju , Gowetski Daniel , Holland-Linn Janel , Hong Jin Sung , Horwitz Joe , Ivleva Vera , Kueltzo Lisa , Lambert Nadji , LaPanse Alaina , Lawlor Heather , Leach Kristin , Lee James , Lei Paula , Li Yile , Liu Jie (Amy) , Manceva Slobodanka , Patel Aakash , Ragunathan Rahul , Romaine Lori , Rosales Erwin , Schneck Nikki , Shadrick William , Shaddeau Andrew , Upadhyay Sudesh , Vickery Karen , Wang Xiangchun (Eric) , Wang Xin , Yang Jack , Yang Rong (Sylvie) , Yang Yanhong , Yi Yansong , Zhao Weidong , Zhao Zhong 
Published: April 2023

Influenza vaccines could be improved by platforms inducing cross-reactive immunity. Immunodominance of the influenza hemagglutinin (HA) head in currently licensed vaccines impedes induction of cross-reactive neutralizing stem-directed antibodies. A vaccine without the variable HA head domain has the potential to focus the immune response on the conserved HA stem. This first-in-human dose-escalation open-label phase 1 clinical trial (NCT03814720) tested an HA stabilized stem ferritin nanoparticle vaccine (H1ssF) based on the H1 HA stem of A/New Caledonia/20/1999. Fifty-two healthy adults aged 18 to 70 years old enrolled to receive either 20 μg of H1ssF once (
n
 = 5) or 60 μg of H1ssF twice (
n
 = 47) with a prime-boost interval of 16 weeks. Thirty-five (74%) 60-μg dose participants received the boost, whereas 11 (23%) boost vaccinations were missed because of public health restrictions in the early stages of the COVID-19 pandemic. The primary objective of this trial was to evaluate the safety and tolerability of H1ssF, and the secondary objective was to evaluate antibody responses after vaccination. H1ssF was safe and well tolerated, with mild solicited local and systemic reactogenicity. The most common symptoms included pain or tenderness at the injection site (
n
 = 10, 19%), headache (
n
 = 10, 19%), and malaise (
n
 = 6, 12%). We found that H1ssF elicited cross-reactive neutralizing antibodies against the conserved HA stem of group 1 influenza viruses, despite previous H1 subtype head-specific immunity. These responses were durable, with neutralizing antibodies observed more than 1 year after vaccination. Our results support this platform as a step forward in the development of a universal influenza vaccine.