Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine.

BACKGROUND: The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. METHODS: We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine. FINDINGS: Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The 'beta variant' RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5. INTERPRETATION: These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial. FUNDING: This work was supported by grants from the Medical Research Future Fund (MRFF) (2005846), The Jack Ma Foundation, National Health and Medical Research Council of Australia (NHMRC; 1113293) and Singapore National Medical Research Council (MOH-COVID19RF-003). Individual researchers were supported by an NHMRC Senior Principal Research Fellowship (1117766), NHMRC Investigator Awards (2008913 and 1173871), Australian Research Council Discovery Early Career Research Award (ARC DECRA; DE210100705) and philanthropic awards from IFM investors and the A2 Milk Company.

Global Pandemic Preparedness: Optimizing Our Capabilities and the Influenza Experience.

The coronavirus disease 2019 (COVID-19) pandemic has prompted rapid investigation and deployment of vaccine platforms never before used to combat human disease. The severe impact on the health system and the high economic cost of non-pharmaceutical interventions, such as lockdowns and international border closures employed to mitigate the spread of COVID-19 prior to the arrival of effective vaccines, have led to calls for development and deployment of novel vaccine technologies as part of a "100-day response ambition" for the next pandemic. Prior to COVID-19, all of the pandemics (excluding HIV) in the past century have been due to influenza viruses, and influenza remains one of the most likely future pandemic threats along with new coronaviruses. New and emerging vaccine platforms are likely to play an important role in combatting the next pandemic. However, the existing well-established, proven platforms for seasonal and pandemic influenza manufacturing will also continue to be utilized to rapidly address the next influenza threat. The field of influenza vaccine manufacturing has a long history of successes, including approval of vaccines within approximately 100 days after WHO declaration of the A(H1N1) 2009 influenza pandemic. Moreover, many advances in vaccine science and manufacturing capabilities have been made in the past decade to optimize a rapid and timely response should a new influenza pandemic threat emerge.

The importance of influenza vaccination during the COVID-19 pandemic.

The COVID-19 pandemic and the measures taken to mitigate its spread have had a dramatic effect on the circulation patterns of other respiratory viruses, most especially influenza viruses. Since April 2020, the global circulation of influenza has been markedly reduced; however, it is still present in a number of different countries and could pose a renewed threat in the upcoming Northern Hemisphere winter. Influenza vaccination remains the most effective preventive measure that we have at our disposal against influenza infections and should not be ignored for the 2021-2022 season.

Vaccine complacency and dose distribution inequities limit the benefits of seasonal influenza vaccination, despite a positive trend in use.

Sustainable demand for seasonal influenza vaccines is a component of national security strategies for pandemic preparedness. However, the ongoing COVID-19 pandemic has revealed many weaknesses in the capacity of countries to design and execute sustainable vaccination programs. An influenza pandemic remains a global threat and yet there is no global monitoring system for assessing progress towards influenza vaccination coverage targets. The International Federation of Pharmaceutical Manufacturers and Associations' (IFPMA) Influenza Vaccine Supply International Task Force (IVS) developed a survey method in 2008 to estimate seasonal influenza vaccination coverage rates, which in turn serves as a crude estimate of pandemic preparedness. It provides evidence to guide expanded efforts for pandemic preparedness, specifically for increasing COVID-19 vaccine immunization levels. Furthermore, the results presented herein serve as a proxy for assessing the state of pandemic preparedness at a global and regional level. This paper adds data from 2018 and 2019 to the previous analyses. The current data show an upward or stable global trend in seasonal influenza vaccine dose distributed per 1,000 population with a 7% increase between 2017 and 2018 and 6% increase between 2018 and 2019. However, considerable regional inequities in access to vaccine persist. Three regions, Africa, the Middle-east, and Southeast Asia together account for 50% of the global population but only 6% of distributed seasonal influenza vaccine doses. This is an important finding in the context of the ongoing COVID-19 pandemic, as distribution of influenza vaccine doses in many ways reflects access to COVID-19 vaccines. Moreover, improving seasonal vaccine uptake rates is critical for optimizing the annual benefits by reducing the huge annual influenza-associated societal burdens and by providing protection to vulnerable individuals against serious complications from seasonal influenza infections.

New Technologies for Influenza Vaccines.

Vaccine development has been hampered by the long lead times and the high cost required to reach the market. The 2020 pandemic, caused by a new coronavirus (SARS-CoV-2) that was first reported in late 2019, has seen unprecedented rapid activity to generate a vaccine, which belies the traditional vaccine development cycle. Critically, much of this progress has been leveraged off existing technologies, many of which had their beginnings in influenza vaccine development. This commentary outlines the most promising of the next generation of non-egg-based influenza vaccines including new manufacturing platforms, structure-based antigen design/computational biology, protein-based vaccines including recombinant technologies, nanoparticles, gene- and vector-based technologies, as well as an update on activities around a universal influenza vaccine.