Infectious Disease · Medical Literature
Safety and immunogenicity of a COVID-19-Influenza Combination nanoparticle vaccine (CIC) containing SARS-CoV-2 recombinant spike and quadrivalent influenza hemagglutinin with Matrix-M® adjuvant: A phase 1/2 clinical trial.
Abstract
Based on viral evolution, increases in seasonal infections, and facilitation of delivery, an annual combination vaccine simultaneously targeting influenza and SARS-CoV-2 would benefit public health. The safety and immunogenicity of a COVID-19-Influenza Combination nanoparticle vaccine (CIC) containing SARS-CoV-2 recombinant spike (rS) to the ancestral strain (Wuhan) and quadrivalent influenza hemagglutinin with a Matrix-M® saponin-based adjuvant were evaluated in a phase 1/2 blinded, randomized trial. The safety, tolerability, and immunogenicity of a CIC two-dose series were assessed and compared with standalone quadrivalent influenza (qNIV) and monovalent COVID-19 (NVX-CoV2373) vaccines. Reactogenicity events, unsolicited adverse events (AEs), antiviral microneutralization responses, hemagglutination-inhibition antibody titers, anti-rS protein immunoglobulin G, and human angiotensin-converting enzyme 2 receptor binding inhibition antibody responses for SARS-CoV-2 were measured. All participants had been previously vaccinated against ancestral SARS-CoV-2. From September 8, 2021, to April 22, 2022, 642 participants were enrolled and randomized into the study; 637 received at least one vaccination. After each dose, CIC formulations induced antibody responses against homologous and heterologous influenza and SARS-CoV-2 strains that were comparable with the references. The CIC vaccine group had similar incidence of solicited and unsolicited AEs as the qNIV and NVX-CoV2373 reference groups. Severe unsolicited AEs only occurred in the CIC group but were infrequent and not considered related to the study vaccine. Overall, CIC formulations displayed reference-comparable safety and immunogenicity and provided data for statistical modeling analyses to optimize influenza hemagglutinin and SARS-CoV-2 rS antigen concentrations for use in phase 2 clinical trials investigating CIC.
Clinical relevance
Is a two-dose COVID-19–Influenza Combination nanoparticle vaccine (CIC) containing ancestral SARS-CoV-2 recombinant spike (rS) and quadrivalent influenza hemagglutinin (HA) with Matrix-M® adjuvant safe, tolerable, and immunogenic compared with standalone quadrivalent influenza (qNIV) and monovalent COVID-19 (NVX-CoV2373) reference vaccines in previously SARS-CoV-2–vaccinated adults aged 50–70 years? __SNAPSHOT__ {"studyDesign":"Phase 1/2 blinded, randomized, dose-finding trial (NCT04961541); design-of-experiments approach used to assess multiple antigen dose combinations with statistical modeling for dose optimization","setting":"10 clinical sites in Australia; September 8, 2021 – April 22, 2022","sampleSize":"n=642 enrolled and randomized; n=637 received at least one vaccination. Randomized across 14 CIC dose/formulation cohorts and 2 reference arms (standalone rS with Matrix-M® [2 doses]; qNIV with Matrix-M® [1 dose]). Individual cohort sizes not reported in abstract.","population":"Adults aged 50–70 years who were baseline seropositive, defined as previously vaccinated against ancestral SARS-CoV-2 at least 8 weeks prior to enrollment. All participants had prior SARS-CoV-2 immune priming; immunologically naive individuals were excluded.","intervention":"CIC two-dose series (Day 0 and Day 56): recombinant SARS-CoV-2 spike (rS; Wuhan ancestral strain) combined with quadrivalent influenza hemagglutinin (HA) nanoparticles and Matrix-M® saponin-based adjuvant. Multiple dose combinations evaluated (rS range 2.5–22.5 µg; HA range 5–60 µg; Matrix-M® 50 µg) using a design-of-experiments approach.","comparator":"Two active reference arms: (1) standalone monovalent COVID-19 vaccine NVX-CoV2373 with Matrix-M® (2-dose series); (2) standalone quadrivalent nanoparticle influenza vaccine (qNIV) with Matrix-M® (1 dose only)","primaryOutcome":"Safety and tolerability (solicited reactogenicity events within 7 days of each dose; unsolicited adverse events) and immunogenicity (antiviral microneutralization responses, hemagglutination-inhibition [HAI] antibody titers, anti-rS IgG, and hACE2 receptor binding inhibition antibody responses) assessed at Days 0, 28, 56, 70, 84, and 182. A formal single primary endpoint was not reported in the abstract.","followUp":"Immunogenicity assessed through Day 182 (approximately 6 months); safety outcomes assessed through at minimum Day 70 per the preliminary data. Full follow-up duration not explicitly stated in the abstract.","fundingSource":"Industry (Novavax, Inc., Gaithersburg, MD, USA); all named authors are Novavax employees holding company stock/bonds"}
Key findings
Of 642 participants randomized, 637 received at least one vaccination. After each dose, CIC formulations induced antibody responses against both homologous and heterologous influenza and SARS-CoV-2 strains that were comparable with standalone reference vaccines. Specific geometric mean titers (GMTs), geometric mean EU (GMEU), seroconversion rates, confidence intervals, and p-values are not reported in the abstract. Antigen interference was detected between rS and HA components within the combination: higher rS doses (>20 µg) in a dose-dependent fashion were required to overcome HA interference and closely match standalone rS IgG reference responses (standalone reference GMEU 16,818 [value from related conference abstract]), while lower-to-intermediate HA doses were necessary to overcome rS interference and approximate standalone HAI reference responses for H3N2 (GMT ~145), H1N1 (GMT ~134), and B-Victoria (GMT ~66); B-Yamagata HAI responses in the CIC were at least 34% lower than the standalone reference (GMT ~101) — values noted as derived from a related conference abstract presentation and labeled accordingly (calculated from conference abstract data). The CIC group had a similar incidence of solicited and unsolicited adverse events as the qNIV and NVX-CoV2373 reference groups. Severe unsolicited AEs occurred only in the CIC group; however, these were infrequent and were assessed as not related to the study vaccine. No serious vaccine-related AEs, NNT, or NNH were reported in the available abstract. Statistical modeling (multiple regression) was applied to generate predictive antibody response surfaces and identify optimized antigen dose combinations for advancement to phase 2 trials.
Practice implications
This phase 1/2 dose-finding trial establishes proof of concept that a protein-based nanoparticle COVID-19–influenza combination vaccine is feasible, well tolerated, and capable of generating immune responses broadly comparable to standalone reference vaccines in previously SARS-CoV-2–vaccinated adults aged 50–70 years. The study did not establish vaccine efficacy against clinical influenza or COVID-19 disease; immunogenicity (antibody titer) endpoints serve as surrogates, and their correlation with clinical protection in this specific combination formulation has not yet been demonstrated. A clinically important observation is antigen interference between rS and HA components, requiring careful dose optimization to achieve adequate responses to both targets simultaneously — notably, B-Yamagata HAI responses appeared meaningfully attenuated compared with the standalone influenza reference. Findings apply specifically to previously immune (vaccine-primed), generally healthy adults aged 50–70 years in Australia; results may not generalize to immunologically naive individuals, immunocompromised patients, children, adults >70 years, or populations with differing prior COVID-19 vaccine histories. All participants had prior SARS-CoV-2 vaccination, which limits the ability to characterize CIC immunogenicity in a naive population. The ancestral Wuhan rS antigen used in this trial is now immunologically mismatched with circulating SARS-CoV-2 variants, which substantially limits current translational relevance of the SARS-CoV-2 immunogenicity data. This trial was designed for dose selection and hypothesis generation, not for definitive regulatory decision-making. Practice should not change on the basis of this study alone; it requires confirmation in adequately powered phase 2/3 trials using updated variant-matched antigens. Only the abstract was available for review; full methods, complete immunogenicity tables, and detailed safety data could not be independently verified. __LIMITATIONS__ Dose-finding design: the trial was not powered for statistical hypothesis testing of immunogenicity non-inferiority or superiority versus licensed vaccines; regression modeling results are hypothesis-generating.,All participants were previously SARS-CoV-2 vaccinated (seropositive at baseline); immunogenicity in naive individuals was not assessed.,The ancestral Wuhan-strain rS antigen is antigenically distant from currently circulating SARS-CoV-2 variants, limiting contemporary relevance of COVID-19 immunogenicity data.,Antigen interference between rS and HA components observed, with B-Yamagata HAI responses notably attenuated vs. standalone reference; clinical significance of this immunological interference is unknown.,No clinical efficacy endpoints (symptomatic influenza, COVID-19 disease); immunogenicity surrogates used throughout.,Single-country trial (Australia) with a geographically and likely ethnically homogeneous sample, limiting generalizability.,Restricted age range (50–70 years); findings may not apply to older adults (>70 years) who bear the greatest burden of both infections.,Short-term safety data reported in the abstract (through Day 70 at minimum); long-term safety and durability of immune responses are incompletely characterized.,All authors are Novavax employees with financial interests in the company (stocks/bonds), representing a high risk of industry bias.,Only the abstract was available for this analysis; complete methodology, blinding procedures, randomization concealment, full safety tables, and statistical analysis plans could not be independently reviewed. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This industry-sponsored phase 1/2 dose-finding trial demonstrates that a protein-based COVID-19–influenza combination nanoparticle vaccine (CIC) with Matrix-M® adjuvant is well tolerated and immunogenic in previously COVID-19–vaccinated adults aged 50–70, with antibody responses broadly comparable to standalone reference vaccines across both antigens. Antigen interference between rS and HA components necessitates careful dose optimization, and B-Yamagata influenza responses were meaningfully attenuated relative to the standalone influenza reference. This study provides sufficient proof-of-concept data to inform dose selection for phase 2 confirmation trials but does not establish clinical efficacy, and the use of the now-outdated Wuhan ancestral rS antigen limits direct relevance to contemporary COVID-19 strain–matched vaccine development.