Immunogenicity of a Two-Dose Human Papillomavirus Vaccine Schedule in HIV-Infected Adolescents with Immune Reconstitution

HIV-infected patients are at increased risk of human papillomavirus (HPV) acquisition and HPV-associated diseases. This study set out to determine whether a two-dose (2D) HPV vaccination schedule was sufficient in HIV-infected adolescents with immune reconstitution (IR) following antiretroviral treatment. Participants aged 9–15 years who had CD4 cell counts > 500 cells/mm3 and HIV-1 RNA < 40 copies/mL for at least one year were assigned to the 2D schedule, while older participants or those without IR received a three-dose (3D) schedule. Antibodies to HPV-16 and -18 were measured using a pseudovirion-based neutralization assay. A total of 96 subjects were enrolled; 31.3% and 68.7% received the 2D and 3D schedule, respectively. Of these, 66.7% and 57.6% of the 2D and 3D participants, respectively, were male. The seroconversion rates for HPV-16 and HPV-18 were 100% in all cases, except for HPV-18 in males who received the 3D schedule (97.4%). In males, the anti-HPV-16 geometric mean titers (GMTs) were 6859.3 (95% confidence interval, 4394.3–10,707.1) and 7011.1 (4648.8–10,573.9) in the 2D and 3D groups (p = 0.946), respectively, and the anti-HPV-18 GMTs were 2039.3 (1432.2–2903.8) and 2859.8 (1810.0–4518.4) in the 2D and 3D (p = 0.313) groups, respectively. In females, the anti-HPV-16 GMTs were 15,758.7 (8868.0–28,003.4) and 26,241.6 (16,972.7–40,572.3) in the 2D and 3D groups (p = 0.197), respectively, and the anti-HPV-18 GMTs were 5971.4 (3026.8–11,780.6) and 9993.1 (5950.8–16,781.1) in the 2D and 3D groups (p = 0.271), respectively. In summary, a 2D schedule is as immunogenic in young adolescents with IR as a 3D schedule in older subjects and those without IR.

A Severe Case of Molluscum Contagiosum Immune Reconstitution Inflammatory Syndrome in a Patient with Human Immunodeficiency Virus

Paradoxical immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-positive patients initiating antiretroviral treatment (ART) is caused by restored immunity to specific antigens, resulting in worsening of a pre-existing infection. Molluscum contagiosum (MC) is commonly noted in HIV-positive individuals but ART alone is usually sufficient to bring about resolution. We present a rare case of severe MC-IRIS that worsened despite immune reconstitution.

Immune Reconstitution Inflammatory Syndrome Induced by Mycobacterium avium Complex Infection Presenting as Chronic Inflammatory Demyelinating Polyneuropathy in a Young AIDS Patient

Antiretroviral therapy (ART) can restore protective immune responses against opportunistic infections (OIs) and reduce mortality in patients with human immunodeficiency virus (HIV) infections. Some patients treated with ART may develop immune reconstitution inflammatory syndrome (IRIS). Mycobacterium avium complex (MAC)-related IRIS most commonly presents as lymphadenitis, soft-tissue abscesses, and deteriorating lung infiltrates. However, neurological presentations of IRIS induced by MAC have been rarely described. We report the case of a 31-year-old man with an HIV infection. He developed productive cough and chronic inflammatory demyelinating polyneuropathy (CIDP) three months after the initiation of ART. He experienced an excellent virological and immunological response. Sputum culture grew MAC. The patient was diagnosed with MAC-related IRIS presenting as CIDP, based on his history and laboratory, radiologic, and electrophysiological findings. Results: Neurological symptoms improved after plasmapheresis and intravenous immunoglobulin (IVIG) treatment. To our knowledge, this is the first reported case of CIDP due to MAC-related IRIS. Clinicians should consider MAC-related IRIS in the differential diagnosis of CIDP in patients with HIV infections following the initiation of ART.

Immune Reconstitution After Allogeneic Haematopoietic Cell Transplantation: From Observational Studies to Targeted Interventions

Immune reconstitution (IR) after allogeneic haematopoietic cell transplantation (HCT) represents a central determinant of the clinical post-transplant course, since the majority of transplant-related outcome parameters such as graft-vs.-host disease (GvHD), infectious complications, and relapse are related to the velocity, quantity and quality of immune cell recovery. Younger age at transplant has been identified as the most important positive prognostic factor for favourable IR post-transplant and, indeed, accelerated immune cell recovery in children is most likely the pivotal contributing factor to lower incidences of GvHD and infectious complications in paediatric allogeneic HCT. Although our knowledge about the mechanisms of IR has significantly increased over the recent years, strategies to influence IR are just evolving. In this review, we will discuss different patterns of IR during various time points post-transplant and their impact on outcome. Besides IR patterns and cellular phenotypes, recovery of antigen-specific immune cells, for example virus-specific T cells, has recently gained increasing interest, as certain threshold levels of antigen-specific T cells seem to confer protection against severe viral disease courses. In contrast, the association between IR and a possible graft-vs. leukaemia effect is less well-understood. Finally, we will present current concepts of how to improve IR and how this could change transplant procedures in the near future.

The effect of age on CD4+ T-cell recovery in HIV-suppressed adult participants: a sub-study from AIDS Clinical Trial Group (ACTG) A5321 and the Bone Loss and Immune Reconstitution (BLIR) study

Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the naïve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells/μL (IQR 442-794) in patients aged 50 years or above and 738 cells/μL (IQR 548-1002) in patients aged 18-35 years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count> 500 cells/μL) between the two age groups were 15, 21 and 26% at year 1, 4 years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery.

An Unusual Presentaton of Tuberculosis with Septic Shock and Immune Reconstitution Inflammatory Syndrome in an Immunocompetent Patient

Tuberculosis presenting as septic shock is a rare entity especially in an immunocompetent patient. It has been reported in only 1% of patients with septic shock. Tuberculosis associated immune reconstitution inflammatory syndrome (IRIS) is the paradoxical worsening of the current condition or the development of new lesions in patients who are on anti-tuberculosis treatment. In non-HIV patients with tuberculosis, the incidence of IRIS is only about 2.4%. We report a 29 year old immunocompetant female who presented with septic shock and on continued evaluation she tested positive for mycobacterium tuberculosis by Genexpert (sensitive to rifampicin) done in BAL fluid. All possible causes for immunodeficiency were ruled out. She was started on Anti-Tuberculosis therapy (ATT) and a month later, patient deteriorated clinically with high spiking temperatures and troublesome constitutional symptoms. Contrast-enhanced computed tomography (CECT) abdomen and chest revealed new onset multiple enlarged necrotic mediastinal, para aortic and hilar lymph nodes. After extensive evaluation including autoimmune profile, fungal culture, viral serology, Positron emission tomography (PET) scan, bone marrow analysis and ruling out all other possible causes for fever, IRIS was suspected and patient was started on steroids along with ATT. There was a drastic improvement in her symptoms within a week. She completed her course of ATT and steroids were gradually tapered. At 2 years of follow up, the patient is doing well.

Infectious complications and vaccines

Infections are a major cause of morbidity and can result in mortality in long-term survivors after allogeneic hematopoietic cell transplantation. Chronic graft-versus-host disease and delayed immune reconstitution are recognized risk factors. Different strategies must be utilized depending on the individual patient's situation but include prolonged antimicrobial prophylaxis and vaccination. Some important infections due to pathogens preventable by vaccination are pneumococci, influenza, varicella-zoster virus, and SARS-CoV-2. Despite the fact that such recommendations have been in place for decades, implementation of these recommendations has been reported to be poor.

Modified T cells as therapeutic agents

Immunotherapy is now a well-established modality in the treatment of cancer. Although several platforms to redirect the immune response exist, the use of genetically modified T cells has garnered particular attention in recent years. This is due, in large part, to their success in the treatment of B-cell malignancies. Adoptively transferred T cells have also demonstrated efficacy in the treatment of systemic viral infections that occur following hematopoietic cell transplantation prior to immune reconstitution. Here we discuss the techniques that enable redirection of T lymphocytes to treat cancer or infection and the current indications for these therapies.