Tick-Borne Encephalitis Virus-Neutralizing Antibodies in Different Immunoglobulin Preparations

Abstract

Patients with primary immunodeficiency (PIDs) depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG). Using the tick-borne encephalitis virus (TBEV), geographic variability in IVIG antibody content was shown. Care should therefore be exercised when treating PIDs in a given geography, as only locally sourced plasma contains the antibody specificities against the circulating pathogens in the given locality. Intravenous immunoglobulin (IVIG) contains the pooled antibodies (Abs) from at least 3,000 to 60,000 healthy blood and plasma donors (10). One of the main areas of IVIG application is as Ab replacement therapy in patients with primary immunodeficiency (PIDs) (22). These persons critically depend on the presence of a variety of antibody specificities in IVIG, which ensures continued protection against any infectious agent they might encounter. As IVIG is manufactured from the variable resource human plasma, lot-to-lot variation in Ab levels of IVIG products are inevitable and have been reported (18). In addition, the Ab content in IVIG differs depending on the geographic origin of the plasma that was used in manufacture: U.S.-sourced (US-IVIG) or European Union-sourced (EU-IVIG) IVIG contains significantly different Ab levels against hepatitis A virus (8, 21), West Nile virus (WNV) (25), cytomegalovirus (21,27), and the different echovirus serotypes (24), with some evidence of a difference in Ab content for measles and rubella (21). The reason for this geographic variability in IVIG Ab content is often not clear, yet one of the more obvious variables affecting the quantity and specificity of Abs in IVIG is the endemicity of a pathogen, where a change in the temporal or geographic pattern of virus circulation affects the antibody content of the final IVIG. When a virus or microbial agent is expanding its geographical range, exposure of the formerly naïve population to this novel agent is reflected in the Ab content of IVIG. This was demonstrated, e.g., for US-IVIG after the introduction of WNV into the United States in 1999 (4,25,31) and recently also for EU-IVIG, where increasing WNV-neutralizing Ab titers were detected in EU-IVIG lots manufactured after 2009, even though no human WNV infections have yet been reported from the countries in which the plasma was sourced (31).To further increase the understanding of the geographical difference in IVIG Ab content, we determined the neutralizing Ab titers of IVIG preparations for tick-borne encephalitis virus (TBEV). This member of the Flaviviridae, for which three subtypes (European, Siberian, and Far Eastern) are distinguished, may cause tick-borne encephalitis (TBE), a potentially serious neurological disease with high fever and encephalitis (33), while 70 to 95% of human infections in regions in which the virus is endemic are either subclinical or totally asymptomatic (12). During the last 30 years, TBE morbidity has increased by 400% in Europe (36), and TBEV is currently expanding from its geographical range in Central...

Affinity-Purified Respiratory Syncytial Virus Antibodies from Intravenous Immunoglobulin Exert Potent Antibody-Dependent Cellular Cytotoxicity

“…The content of antibodies against microbial antigens is influenced by the endemic nature of the pathogens and vaccination history of the population. Several studies have documented the existence of antibodies against pathogens including West Nile Virus, hepatitis B virus, cytomegalovirus and Plasmodium [7]–[12]. The current study was thus designed to determine the presence of RSV-specific antibodies and their functional potency after antigen-specific purification in various commercially available IVIg preparations.…”

Immunoglobulins and virus antibody titers: of past needs, current requirements, and future options

“…9,11 In Central and Eastern Europe and Northern Asia, the circulation of tickborne encephalitis virus (TBEV) and the widespread use of a vaccine against this Flavivirus, which is closely related to WNV, resulted in significant TBEV neutralization capacity of EU plasma-derived Ig lots, whereas TBEV-specific antibodies were not present in Ig lots fractionated from plasma sourced in the United States, as TBEV is not present in this geography. 12 In fact, the approach of using individual lots of Ig as samples in seroepidemiologic investigations, with each lot of Ig reflective of the serostatus of several thousand plasma donors, did allow for the first identification of WNV circulation in humans in Central Europe. 13 In the study presented here, virus antibody titers in Ig preparations other than to the polio virus and the measles virus were investigated, with the intent of identifying potential future alternatives suitable for functional Ig lot release testing, which may in addition provide relevant information for current Ig users as well as the concerned medical community.…”

May early intervention with high dose intravenous immunoglobulin pose a potentially successful treatment for severe cases of tick-borne encephalitis?

“…If this is the case, it may be important to obtain immunoglobulins from blood donors vaccinated against TBE [27], in analogy to anti-WNV hyper immune IVIG. Furthermore, clinical symptoms, CSF laboratory parameters including neopterin, together with a characteristic acute phase MRI may allow an early tentative diagnosis, even before serological test results are returned, and may indicate an early intervention with high dose IVIG.…”

“…While the dysautonomic symptoms improved and cardiac arrhythmia disappeared, the other neurologic symptoms did not change, and a post-encephalitic syndrome persisted that forced the patient into early retirement [26]. In this context, it may be interesting to note that actual IVIG preparations contain different levels of anti-TBE antibodies, depending on their geographical origin [27]. …”