Adjuvants in preclinical and clinical development: The do and don’t

It is clearly accepted that all vaccines are adjuvanted (endogenously: part of the pathogen or exogenously: added to the antigen formulation) except for a few vaccines such as liquid Hib or non aluminic Meningitis vaccines .It is also recognized that the vast majority of recombinant vaccines if not all, will require an adjuvant to induce an immune response which will be adequate in quality and quantity. Over the past 3 decades, adjuvants have become increasingly important and central to the development of new and improved vaccines. Although the introduction of exogenously adjuvanted vaccine has been slow and steady, 7 licensed vaccines based in the adjuvanted approach are now licensed, and the number eaching late development phase continue to increase. Their introduction into vaccines has added complexity to the development of vaccines in terms of formulation, preclinical and safety evaluation both preclinically and clinically. Challenges however remain and should be understood and overcome when embarking in the development of a new adjuvant antigen combination. It is only the combination of the right antigen and the right adjuvant that will lead to an efficacious vaccine, in that sense, one cannot be assessed without the other, in particular in the context of the formulation. Special consideration need to be taken when defining and evaluating the formulation aspect of the vaccine.The preclinical evaluation needs to take into account the nature of the adjuvant used and its potential differences between species. Understanding adjuvant mode of action has therefore become crucial, with the realization that differences existed between animals and humans making extrapolation between preclinical and clinical not always possible. The use of adjuvants in new vaccines has highlighted the need to define preclinical and clinical safety evaluation methods as compared to therapeutic small molecules This presentation will review the challenges faced with the development of adjuvanted vaccines, from their inception to current days, and path that could be followed

Vaccine safety evaluation: Practical aspects in assessing benefits and risks

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Modulation of the vertical particle transfer efficiency in the oxygen minimum zone off Peru

The fate of the organic matter (OM) produced by marine life controls the major biogeochemical cycles of the Earth's system. The OM produced through photosynthesis is either preserved, exported towards sediments or degraded through remineralisation in the water column. The productive eastern boundary upwelling systems (EBUSs) associated with oxygen minimum zones (OMZs) would be expected to foster OM preservation due to low O2 conditions. But their intense and diverse microbial activity should enhance OM degradation. To investigate this contradiction, sediment traps were deployed near the oxycline and in the OMZ core on an instrumented moored line off Peru. Data provided high-temporal-resolution O2 series characterising two seasonal steady states at the upper trap: suboxic ([O2]  50%) and remineralisation (intermediate Teff 20  50%) has been reported in summer and winter associated with extreme limitation in O2 concentrations or OM quantity for OM degradation. However, higher levels of O2 or OM, or less refractory OM, at the oxycline, even in a co-limitation context, can decrease the OMZ transfer efficiency to below 50%. This is especially true in summer during intraseasonal wind-driven oxygenation events. In late winter and early spring, high oxygenation conditions together with high fluxes of sinking particles trigger a shutdown of the OMZ transfer (Teff < 6%). Transfer efficiency of chemical elements composing the majority of the flux (nitrogen, phosphorus, silica, calcium carbonate) follows the same trend as for carbon, with the lowest transfer level being in late winter and early spring. Regarding particulate isotopes, vertical transfer of δ15N suggests a complex pattern of 15N impoverishment or enrichment according to Teff modulation. This sensitivity of OM to O2 fluctuations and particle concentration calls for further investigation into OM and O2-driven remineralisation processes. This should include consideration of the intermittent behaviour of OMZ towards OM demonstrated in past studies and climate projections

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Innate immunity and vaccine adjuvants: From concepts to the development of a unique adjuvant system as04 used for the formulation of a human papillomavirus (hpv) vaccine

New vaccine technology has led to vaccines containing highly purified antigens with improved safety profiles, but increased antigen purity often results in weakened immunogenicity. A better understanding of innate and adaptive immunity and their interaction at the molecular level has led to the use of innovative adjuvants combined with careful an- tigen selection. Adjuvants can be used to amplify the immune response, and the combination of antigens with more than one adjuvant, the Adjuvant System approach, allows the development of vaccines which generate specific and effective immune responses adapted to both the pathogen and the target population. One of those Adjuvant Systems is AS04, a combination of the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. The added value of MPL in AS04-based formulation above Aluminium was evidenced for a prophylactic human papillomavirus (HPV)-16/18 vaccine by higher vaccine-elicited antibody responses, as well as the induction of higher levels of memory B-cells. This review focuses on the role of AS04 for development of Cervarix™, a vaccine for the prevention of cervical cancer. © 2010 Bentham Science Publishers Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Boosting vaccine power

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

From discovery to licensure, the Adjuvant System story

Adjuvants are substances added to vaccines to improve their immunogenicity. Used for more than 80 years, aluminum, the first adjuvant in human vaccines, proved insufficient to develop vaccines that could protect against new challenging pathogens such as HIV and malaria. New adjuvants and new combinations of adjuvants (Adjuvant Systems) have opened the door to the delivery of improved and new vaccines against re-emerging and difficult pathogens. Adjuvant Systems concept started through serendipity. The access to new developments in technology, microbiology and immunology have been instrumental for the dicephering of what they do and how they do it. This knowledge opens the door to more rational vaccine design with implications for developing new and better vaccines