Malaria transmission-blocking conjugate vaccine in ALFQ adjuvant induces durable functional immune responses in rhesus macaques

Malaria transmission-blocking vaccines candidates based on Pfs25 and Pfs230 have advanced to clinical studies. Exoprotein A (EPA) conjugate of Pfs25 in Alhydrogel® developed functional immunity in humans, with limited durability. Pfs230 conjugated to EPA (Pfs230D1-EPA) with liposomal adjuvant AS01 is currently in clinical trials in Mali. Studies with these conjugates revealed that non-human primates are better than mice to recapitulate the human immunogenicity and functional activity. Here, we evaluated the effect of ALFQ, a liposomal adjuvant consisting of TLR4 agonist and QS21, on the immunogenicity of Pfs25-EPA and Pfs230D1-EPA in Rhesus macaques. Both conjugates generated strong antibody responses and functional activity after two vaccinations though activity declined rapidly. A third vaccination of Pfs230D1-EPA induced functional activity lasting at least 9 months. Antibody avidity increased with each vaccination and correlated strongly with functional activity. IgG subclass analysis showed induction of Th1 and Th2 subclass antibody levels that correlated with activity.

Judgment on Foreign Soldiers' Immunity for War Crimes Committed Abroad (BGH)

On January 28, 2021, the German Federal Court of Justice, or Bundesgerichtshof (BGH), Germany's highest court of ordinary jurisdiction, delivered its judgment in Case 3 StR 564/19 pertaining to questions of universal jurisdiction over international crimes and the extent to which foreign soldiers would be barred from prosecution in Germany based on claims of (functional) immunity for war crimes committed abroad. The decision strikes at the heart of a debate where such exceptions to immunity (ratione materiae) are yet to be uniformly agreed upon at an international level; it also comes on the verge of a number of related judgments that are pending both in German and other European courts. In the present case, the BGH held that according to the general rules of international law, criminal prosecution in Germany for war crimes committed abroad would not be precluded based on the notion of functional immunity, “when the acts have been committed by a foreign, lower-ranking defendant in the exercise of foreign sovereign activity.” Neither the BGH nor Germany's supreme guardian of the “Basic Law,” the Federal Constitutional Court, or Bundesverfassungsgericht (BVerfG), has previously pronounced itself on questions of functional immunity in criminal proceedings.

The Arbitral Award in the Enrica Lexie Case and its Questionable Recognition of Functional Immunity to the Italian Marines Under Customary International Law

The dispute between Italy and India on the Enrica Lexie incident has finally been decided by the Award handed down on 21 May 2020 by the Arbitral Tribunal to which the Parties had referred the case. After having concluded that it had jurisdiction on the issue of the immunity of the two Italian marines involved in the case at hand, the majority judgment (by three votes to two) affirmed that under customary international law the latter enjoyed functional immunity from the criminal jurisdiction of India. This article will argue that the Arbitral Tribunal’s conclusions are unconvincing, first and foremost, considering that, based on State practice, it is not possible to affirm without reservations that a settled customary rule exists under international law conferring immunity to all State officials, and regardless of the type of functions they perform. In fact, immunity has often been recognized as applying only to certain categories of State officials, and on the basis of the governmental nature of the functions they perform on behalf of the State. Given the doubtful existence under customary international law of a clear rule establishing the functional immunity of all State officials, for all the acts performed in the exercise of their functions, this article argues that the Arbitral Tribunal should have firstly ascertained the existence of a specific customary rule on the immunity of the military abroad, together with the exact content of such rule and, secondly, whether this was applicable in the case of the Enrica Lexie. As current practice stands, military forces abroad are entitled to immunity only under specific circumstances, which do not seem to occur in the present case. In particular, this article maintains that the Italian marines were not entitled to functional immunity. While the acts they performed did indeed fall within their typical functions, they were exercised on behalf of a private subject and not on behalf of the Italian State.

The Enrica Lexie Award Amid Jurisdictional and Law of the Sea Issues

This article analyzes the Enrica Lexie Arbitral Award, first of all, in relation to international law issues concerning the application of the United Nations Convention on the Law of the Sea (UNCLOS). The article then focuses on the question of the functional immunity of the two marines, from the point of view of the Tribunal’s assertion of its incidental jurisdiction to deal with the matter, as well as of the Tribunal’s affirmation of the existence of a customary international law rule applicable in the present case. Both conclusions appear unconvincing, also in light of the role of the two marines on board a merchant ship. In any case, the fact remains that the judgment has the merit of finally putting an end to a long-standing dispute, to the satisfaction of the two parties involved.

Functional Immunity of the Marines on the Enrica Lexie: A Reply To Raffaella Nigro

This article is a short reply to Raffaella Nigro’s assessment of the Arbitral Tribunal award in the Enrica Lexie case. Professor Nigro analyzes the rule of functional immunity of State officials from foreign criminal jurisdiction and argues that it cannot be applied to the two marines, even supposing that military personnel are covered by such a rule. Professor Nigro bases this conclusion on the facts that the marines were stationed on a commercial vessel and were servicing the interests of the private shipowner. In reply, this author reaffirms the existence of a rule of customary international law on functional immunity and argues that military personnel assigned to commercial vessels are carrying out these duties in order to protect Italian interests and contribute to the defeat of piracy. Therefore, the marines on board the Enrica Lexie were (and still remain) under the protection of the rule on immunity from foreign criminal jurisdiction.

Multicomponent Vaccines against Group A Streptococcus Can Effectively Target Broad Disease Presentations

Group A Streptococcus (GAS) is an important global human pathogen, with a wide range of disease presentations, from mild mucosal infections like pharyngitis to invasive diseases such as toxic shock syndrome. The effect on health and mortality from GAS infections is substantial worldwide, particularly from autoimmune sequelae-like rheumatic heart disease (RHD), and there is currently no licenced vaccine. We investigated protein antigens targeting a broad range of GAS disease presentations as vaccine components in individual and combination formulations. The potency and functional immunity generated were evaluated and compared between groups. Antibodies against all components were found in pooled human IgG (IVIG) and an immune response generated following the subcutaneous immunisation of mice. A combination immunisation showed a reduction in IgG response for SpyCEP but an increase for Cpa and Mac-1 (IdeS). An opsonophagocytosis assay (OPA) showed the killing of GAS with immune sera against M protein and combination groups, with a lower killing activity observed for immune sera against other individual antigens. Specific antigen assays showed functional immunity against SpyCEP and Mac-1 from both individual and combination immunisations, with the activity correlating with antibody titres. However, efficient blocking of the binding activity of Cpa to collagen I and fibronectin could not be demonstrated with immune sera or purified IgG. Our data indicate that combination immunisations, while effective at covering a broader range of virulence factors, can also affect the immune response generated. Further, our results showed that an OPA alone is inadequate for understanding protection from vaccination, particularly when considering protection from immune evasion factors and evaluation of the colonisation leading to pharyngitis.

Dynamic Changes of the Bone Marrow Niche: Mesenchymal Stromal Cells and Their Progeny During Aging and Leukemia

Mesenchymal stromal cells (MSCs) are a heterogenous cell population found in a wide range of tissues in the body, known for their nutrient-producing and immunomodulatory functions. In the bone marrow (BM), these MSCs are critical for the regulation of hematopoietic stem cells (HSC) that are responsible for daily blood production and functional immunity throughout an entire organism’s lifespan. Alongside other stromal cells, MSCs form a specialized microenvironment BM tissue called “niche” that tightly controls HSC self-renewal and differentiation. In addition, MSCs are crucial players in maintaining bone integrity and supply of hormonal nutrients due to their capacity to differentiate into osteoblasts and adipocytes which also contribute to cellular composition of the BM niche. However, MSCs are known to encompass a large heterogenous cell population that remains elusive and poorly defined. In this review, we focus on deciphering the BM-MSC biology through recent advances in single-cell identification of hierarchical subsets with distinct functionalities and transcriptional profiles. We also discuss the contribution of MSCs and their osteo-adipo progeny in modulating the complex direct cell-to-cell or indirect soluble factors-mediated interactions of the BM HSC niche during homeostasis, aging and myeloid malignancies. Lastly, we examine the therapeutic potential of MSCs for rejuvenation and anti-tumor remedy in clinical settings.

State Immunity in Relation to Damage Caused by Legislation

Whenever we mention damage caused by legislation, the question arises if it is possible to talk about the liability of what defines the rules of liability. Is the civil court competent in deciding in these cases at all? It is doubtless that the concept of damage caused by legislation is on the threshold between public and private law, and immunity decides whether it is one or the other. More and more articles are written on the topic of damage caused by legislation, and their approaches to the root of the problem are all different. In this study, by analysing the issues of immunity with regard to damage caused by legislation, I try to reveal the past and present of regulations, and in this way the damage caused by legislation can be separated from the state’s functional immunity.

Evaluating Functional Immunity Following Encapsulated Bacterial Infection and Vaccination

Encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis cause significant morbidity and mortality in young children despite the availability of vaccines. Highly specific antibodies are the primary mechanism of protection against invasive disease. Robust and standardised assays that measure functional antibodies are also necessary for vaccine evaluation and allow for the accurate comparison of data between clinical studies. This mini review describes the current state of functional antibody assays and their importance in measuring protective immunity.

Structural identification of neutralizing antibodies induced by nucleic acid encoded native-like trimer

Despite extensive efforts, an efficacious HIV vaccine remains elusive. HIV Envelope (Env) is the target of all known neutralizing antibodies. Stabilizing Env into native-like trimer (NLT) conformations is required for recombinant protein immunogens to induce autologous neutralizing antibodies(nAbs) against difficult to neutralize HIV strains (tier-2) in rabbits and non-human primates. However, mice are the most cost effective and widely used vaccine model and mouse immunizations with NLTs have generally failed to induce tier-2 nAbs. Here, we explored if DNA-encoded NLTs would fold properly in vivo and induce an informed humoral response. We observed DNA encoding a BG505 NLT induces autologous tier-2 nAbs in mice, identified murine monoclonal neutralizing antibodies, mapped the responses to a new murine neutralizing Env C3/V5 epitope and determined the structures of Env-nAbs complexes. Beyond potential functional immunity gains, DNA vaccines permit in vivo folding of structured antigens and provide significant cost and speed advantages for enabling rapid evaluation of new HIV vaccines.