A low dose of RBD and TLR7/8 agonist displayed on influenza virosome particles protects rhesus macaque against SARS-CoV-2 challenge.

Influenza virosomes serve as antigen delivery vehicles and pre-existing immunity toward influenza improves the immune responses toward antigens. Here, vaccine efficacy was evaluated in non-human primates with a COVID-19 virosome-based vaccine containing a low dose of RBD protein (15 µg) and the adjuvant 3M-052 (1 µg), displayed together on virosomes. Vaccinated animals (n = 6) received two intramuscular administrations at week 0 and 4 and challenged with SARS-CoV-2 at week 8, together with unvaccinated control animals (n = 4). The vaccine was safe and well tolerated and serum RBD IgG antibodies were induced in all animals and in the nasal washes and bronchoalveolar lavages in the three youngest animals. All control animals became strongly sgRNA positive in BAL, while all vaccinated animals were protected, although the oldest vaccinated animal (V1) was transiently weakly positive. The three youngest animals had also no detectable sgRNA in nasal wash and throat. Cross-strain serum neutralizing antibodies toward Wuhan-like, Alpha, Beta, and Delta viruses were observed in animals with the highest serum titers. Pro-inflammatory cytokines IL-8, CXCL-10 and IL-6 were increased in BALs of infected control animals but not in vaccinated animals. Virosomes-RBD/3M-052 prevented severe SARS-CoV-2, as shown by a lower total lung inflammatory pathology score than control animals.

Respiratory syncytial virus subunit vaccines based on the viral envelope glycoproteins intended for pregnant women and the elderly.

Introduction: Respiratory syncytial virus (RSV) causes high morbidity and mortality rates among infants, young children, and the elderly worldwide. Unfortunately, a safe and effective vaccine is still unavailable. In 1966, a formalin-inactivated RSV vaccine failed and resulted in the death of two young children. This failure shifted research toward the development of subunit-based vaccines for pregnant women (to passively vaccinate infants) and the elderly. Among these subunit-based vaccines, the viral envelope glycoproteins show great potential as antigens. Areas covered: In this review, progress in the development of safe and effective subunit RSV vaccines based on the viral envelope glycoproteins and intended for pregnant women and the elderly, are reviewed and discussed. Studies published in the period 2012-2018 were included. Expert opinion: Researchers are close to bringing safe and effective subunit-based RSV vaccines to the market using the viral envelope glycoproteins as antigens. However, it remains a major challenge to elicit protective immunity, with a formulation that has sufficient (storage) stability. These issues may be overcome by using the RSV fusion protein in its pre-fusion conformation, and by formulating this protein as a dry powder. It may further be convenient to administer this powder via the pulmonary route.

Adjuvanted influenza vaccines.

The search for adjuvants has been stimulated by the need to ensure greater protection against influenza among subjects who show a reduced immune response to conventional influenza vaccines. Aluminum salts have long been used but are not considered satisfactory. This has led to the development of other possible compounds, sometimes on the basis of new knowledge concerning the mechanisms regulating the immune response to infections. Some of the new adjuvants (emulsions and virosomes) have been widely evaluated, and the apparently good results have led to the registration of adjuvanted influenza vaccines for use in humans, at least in some countries and in some subjects. In other cases, the adjuvants have been mainly or exclusively studied in experimental animals, and are unlikely to be used in humans in the near future. However, even in the case of those for which a considerable amount of data are available, assessments of their superiority over conventional influenza vaccines have mainly been based on immunogenicity studies, and have not been confirmed by comparative, randomized, double-blind clinical trials. Moreover, the very few human data comparing different adjuvants are frequently conflicting. The aim of this review is to discuss the characteristics and advantages of the adjuvants that have so far been used and to describe some of the new adjuvants that are still in the development phase.

Virosome-formulated Plasmodium falciparum AMA-1 & CSP derived peptides as malaria vaccine: randomized phase 1b trial in semi-immune adults & children.

BACKGROUND: This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children. METHODS: The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5-9 years) living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90. RESULTS: No serious or severe adverse events (AEs) related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014). In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR  = 0.50 [95%-CI: 0.29-0.88], p = 0.02). CONCLUSION: These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines. TRIAL REGISTRATION: ClinicalTrials.gov NCT00513669.

The virosomal adjuvanted influenza vaccine.

IMPORTANCE OF THE FIELD: The protection conferred by influenza vaccines varies for several reasons, for example the age or degree of immune depression of the recipient. All currently available seasonal influenza vaccines are safe and substantially effective in preventing influenza in healthy people. However, elderly people and patients with chronic diseases or immune system defects need a more effective vaccine to avoid serious risks from influenza and its complications. Research has been undertaken to improve the efficacy of vaccination. Recent research includes the use of new adjuvants or antigen-presenting strategies. AREAS COVERED IN THIS REVIEW: The virosomal adjuvanted subunit influenza vaccine has been studied in groups for whom vaccination is recommended. We describe virosomal technology, including production and mode of action, as well as the available efficacy, immunogenicity and safety data, with the aim of understanding the benefits of this vaccine's use. WHAT THE READER WILL GAIN: A review of published data on efficacy, immunogenicity and safety from sponsor- and investigator- driven studies, focusing on recent publications. TAKE HOME MESSAGE: The vaccine was generally very immunogenic and safe in all investigated populations. Its ability to induce protective antibody titers has been shown to exceed that of conventional influenza vaccines in elderly people and individuals with little or no prior exposure to the viral strains.

Eleven years of Inflexal V-a virosomal adjuvanted influenza vaccine.

Since the introduction to the Swiss market in 1997, Crucell (former Berna Biotech Ltd.), has sold over 41 million doses worldwide of the virosomal adjuvanted influenza vaccine, Inflexal V. Since 1992, 29 company sponsored clinical studies investigating the efficacy and safety of Inflexal V have been completed in which 3920 subjects participated. During its decade on the market, Inflexal V has shown an excellent tolerability profile due to its biocompatibility and purity. The vaccine contains no thiomersal or formaldehyde and its purity is reflected in the low ovalbumin content. By mimicking natural infection, the vaccine is highly efficacious. Inflexal V is the only adjuvanted influenza vaccine licensed for all age groups and shows a good immunogenicity in both healthy and immunocompromised elderly, adults and children. This review presents and discusses the experience with Inflexal V during the past decade.

Influenza virosomes as a combined vaccine carrier and adjuvant system for prophylactic and therapeutic immunizations.

Influenza virosomes are an efficient antigen carrier and adjuvant system that are approved for the use in human vaccines. Structurally, virosomes are spherical vesicles of approximately 150 nm in diameter, composed of a lipid membrane with integrated envelope proteins derived from influenza virus, predominantly hemagglutinin. The particle structure, together with the functions of hemagglutinin--receptor binding, pH-dependent fusion activity and immunostimulation--is responsible for the adjuvant effect of virosomes. In contrast to most other virus-like particles, virosomes are semisynthetic particles reconstituted in vitro from lipids and from virus-derived proteins. The production process has proven to be robust at industrial scale and fully compatible with Good Manufacturing Practice guidelines. At the same time, the formulation procedure is sufficiently flexible to allow modifications of the composition and structure for the intended use, including the positioning of the antigens of interest.