Eradicating hepatitis B virus: The critical role of preventing perinatal transmission.

Prevention of hepatitis B virus (HBV) transmission from infected mothers to their newborns is critical to HBV control and eventual eradication. Mother-to-child perinatal transmission causes the highest chronic carrier rate (>85%) with a high rate of subsequent chronic liver disease and hepatocellular carcinoma. This risk is reduced by 90% with HBV vaccine given along with hepatitis B immune globulin (HBIG) starting at birth. New analyses of our data from US trials of HBIG and HBV vaccine in high-risk infants revealed better efficacy with yeast-recombinant vaccine than plasma-derived vaccine, especially in preventing late onset infections, with evidence that vaccine prevented transmission of maternal HBV infection with the glycine to arginine mutation in surface antigen codon 145 (sG145R). Most late infections with sG145R were in vaccine non-responders, suggesting escape from HBIG rather than from vaccine-induced antibody. Our findings also help explain survey results from Taiwan following universal childhood immunization implemented in the mid-1980s. We conclude that current vaccines will remain effective against surface antigen mutants. Anti-viral drugs in high-risk pregnant women, in combination with newborn HBIG and vaccine, show promise for eliminating residual breakthrough neonatal infections, critical to meeting WHO 2030 goals and for eradicating HBV.

Adverse effects of plasma transfusion.

Plasma utilization has increased over the past two decades, and there is a growing concern that many plasma transfusions are inappropriate. Plasma transfusion is not without risk, and certain complications are more likely with plasma than other blood components. Clinical and laboratory investigations of the patients suffering reactions after infusion of fresh-frozen plasma (FFP) define the etiology and pathogenesis of the panoply of adverse effects. We review here the pathogenesis, diagnosis, and management of the risks associated with plasma transfusion. Risks commonly associated with FFP include: 1) transfusion-related acute lung injury, 2) transfusion-associated circulatory overload, and 3) allergic and/or anaphylactic reactions. Other less common risks include 1) transmission of infections, 2) febrile nonhemolytic transfusion reactions, 3) red blood cell alloimmunization, and 4) hemolytic transfusion reactions. The effects of pathogen inactivation or reduction methods on these risks are also discussed. Fortunately, a majority of the adverse effects are not lethal and are adequately treated in clinical practice.

Derivation of non-infectious envelope proteins from virions isolated from plasma negative for HIV antibodies.

Natural membrane-bound HIV-1 envelope proteins (mHIVenv) could be used to produce an effective subunit vaccine against HIV infection, akin to effective vaccination against HBV infection using the hepatitis B surface antigen. The quaternary structure of mHIVenv is postulated to elicit broadly neutralizing antibodies protective against HIV-1 transmission. The founder virus transmitted to infected individuals during acute HIV-1 infection is genetically homogeneous and restricted to CCR5-tropic phenotype. Therefore, isolates of plasma-derived HIV-1 (PHIV) from infected blood donors while negative for antibodies to HIV proteins were selected for expansion in primary lymphocytes as an optimized cell substrate (OCS). Virions in the culture supernatants were purified by removing contaminating microvesicles using immunomagnetic beads coated with anti-CD45. Membrane cholesterol was extracted from purified virions with beta-cyclodextrin to permeabilize them and expel p24, RT and viral RNA, and permit protease-free Benzonase to hydrolyze the residual viral/host DNA/RNA without loss of gp120. The resultant mHIVenv, containing gp120 bound to native gp41 in immunoreactive form, was free from infectivity in vitro in co-cultures with OCS and in vivo after inoculating SCID-hu Thy/Liv mice. These data should help development of mHIVenv as a virally safe immunogen and enable preparation of polyclonal hyper-immune globulins for immunoprophylaxis against HIV-1 infection.

Participating in the evolution of transfusion medicine from a dispensary into a discipline.

Collecting, processing and dispensing blood for hemotherapy has evolved into transfusion medicine (TM), a newly recognized discipline. Joining my efforts to those of collaborators all over the world during this period of transformation, my scientific career spanned from the investigation of the immunogenetics of Bombay (OhOh) blood to the establishment of the academic TM program at the University of California, San Francisco (UCSF) (San Francisco, Calif). The twin discoveries of class-specific antibodies against immunoglobulin A (IgA) causing anaphylactic transfusion reactions and of anti-IgA of limited specificity defining A2m(1) as the first genetic marker of IgA led to the award of the Julliard Prize. My precocious appointment as the head of the Bombay Municipal Blood Center in India launched my academic career in 1969 as the Chief of the blood bank at UCSF Medical Center. Viral hepatitis, then the principal risk of transfusion, engaged me in the molecular analyses of purified hepatitis B virus (HBV) and its surface antigen. Consequently the first HBV vaccine, derived from infected plasma (superseded by cloned HBV envelope protein) and hepatitis B immune globulin were developed for clinical trials that led to Food and Drug Administration-licensed biologic products for prophylaxis and therapy. The advent of HIV/AIDS in the early 1980s raised renewed concern about transfusion safety and led me to push for hepatitis B core antibodies blood screening for improved transfusion safety. The triennial International Symposia on Viral Hepatitis and Liver Disease, which I started in 1972, continue to be the foremost forum for the contemporary assessment of hepatitis prevention and treatment. Besides viral hepatitis, I undertook multiplexed flow cytometric analyses for markers of infection by blood-borne viruses and their polymerase chain reaction-amplified gene products, kinetics of HIV replication in peripheral blood lymphocytes, leukocyte depletion for safer transfusion, and removal/inactivation of blood-borne viruses. The TM training and research programs I initiated at UCSF in the 1980s with National Institutes of Health support enabled me to recruit new faculty members who continue to foster the worldwide advancement of transfusion safety.

Preparation and use of therapeutic antibodies primarily of human origin.

Therapeutic antibodies include polyclonal immunoglobulins isolated from regular or high-titered human plasma, sera from immunized animals, and monoclonal antibodies. This array of therapeutic antibodies is used for the prevention and treatment of many infectious diseases, antibody immunodeficiencies, autoimmune and inflammatory diseases, neurological disorders, and cancers. Polyclonal human immunoglobulins are available for intramuscular injection (IGIM), intravenous infusion (IGIV) and subcutaneous infusion (SCIG). We review these products and detail the therapeutic use of polyclonal human antibodies in the treatment of antibody immunodeficiencies, including their occasional local side effects (tenderness, sterile abscesses), minor systemic side effects (chills, muscle aches, malaise, headaches) and major side effects (aseptic meningitis, nephropathy, thrombosis).

Possible transmission of human immunodeficiency virus-1 infection from an elite controller to a patient who progressed to acquired immunodeficiency syndrome: a case report.

INTRODUCTION: Most individuals infected with human immunodeficiency virus-1, in the absence of antiretroviral therapy, exhibit persistent virus replication and declining CD4+ cell numbers, and progress to acquired immunodeficiency syndrome within 10 years of infection. Elite controllers are rare individuals with human immunodeficiency virus-1 infection who can maintain undetectable plasma virus levels and remain asymptomatic without antiretroviral therapy. It has been proposed that elite controllers benefit from being infected with attenuated human immunodeficiency virus-1 variants. CASE PRESENTATION: A 31-year-old African woman presented with human immunodeficiency virus-1 infection during pregnancy and was diagnosed with acquired immunodeficiency syndrome. Subsequently, her husband, a 31-year-old African man, was tested and found to be seropositive for human immunodeficiency virus-1. His plasma human immunodeficiency virus-1 ribonucleic acid level was found to be below the limit of detection of the clinical assay. CONCLUSION: This report provides evidence for the first described case of human immunodeficiency virus-1 infection possibly transmitted from an elite controller to a patient who progressed to acquired immunodeficiency syndrome. This observation strengthens the case against avirulence as a mechanism that protects elite controllers.