[Posted 05/Aug/2022]

AUDIENCE: Infectious Disease, Ob/Gyn, Family Medicine

KEY FINDINGS: As of July 29, 2022, the Centers for Disease Control and Prevention (CDC) and state and local public health partners are reporting 5,189 cases of Monkeypox virus infections in the United States across 47 states, Washington, D.C., and Puerto Rico. CDC is also reporting multiple outbreaks of monkeypox that have been reported globally in 71 countries that do not normally report monkeypox activity. On Friday, July 22, CDC reported the first two cases of monkeypox in children in the United States during the current outbreak. This Health Alert Network (HAN) Health Update serves to alert clinicians to clinical considerations for preventing, diagnosing, and managing monkeypox in people with HIV, children, adolescents, and people who are pregnant or breastfeeding.

BACKGROUND: Since May 2022, CDC has been urging healthcare providers in the United States to be on alert for patients who have rash illnesses consistent with monkeypox. People with HIV, individuals who are immunocompromised, children, adolescents, and people who are pregnant or breastfeeding may be at risk for increased disease severity and adverse health outcomes associated with monkeypox infection. Clinicians should be familiar with unique clinical considerations for monkeypox in these patient populations. A broad diagnostic approach is encouraged to distinguish Monkeypox virus infection from other causes of fever and rash illness. Testing should be performed on persons for whom monkeypox is suspected based on clinical presentation or epidemiologic criteria. Clinicians should consult their state or territorial health department (State Contacts) or CDC through the CDC Emergency Operations Center (770-488-7100) as soon as monkeypox is suspected.

DETAILS: CDC has issued clinical considerations for monkeypox infection in multiple populations including: people with HIV, children and adolescents, and people who are pregnant or breastfeeding. These newly released clinical considerations complement existing clinical guidance for managing monkeypox and provide information on signs and symptoms of Monkeypox virus infection; pre- and post-exposure prophylaxis; treatment; and infection control in these populations.

Recommendations and Information for Healthcare Providers on Monkeypox in People with HIV

In the current outbreak, available international summary surveillance data in the CDC-issued clinical considerations for people with HIV indicate 30-51% HIV prevalence among persons with monkeypox for whom HIV status was known. It is currently unknown whether HIV infection affects a person's risk of acquiring Monkeypox virus infection and developing disease after exposure.

Persons with advanced and uncontrolled HIV might be at higher risk for severe or prolonged monkeypox disease. Therefore, prophylaxis (e.g., vaccination), medical treatment and close monitoring are a priority for this population. Compared with other persons with monkeypox, case reports among persons with inadequately treated HIV who have CD4 counts <=350 per mm³ reported higher rates of secondary bacterial infection, more prolonged illness (and thereby also longer period of infectiousness), as well as a higher likelihood of a confluent or partially confluent rash, rather than discrete lesions. In contrast, recent reports of patients with HIV infection and monkeypox who are on effective antiretroviral therapy (ART) have noted no deaths or evident excess hospitalizations to date. Providers should consider both viral suppression and CD4 count in weighing the risk of severe outcomes from monkeypox for any patient with HIV.

The rash of monkeypox can be confused with other rash illnesses that are considered in people with HIV, including herpes zoster (shingles), scabies, molluscum contagiosum, herpes, syphilis, chancroid, lymphogranuloma venereum, allergic skin rashes, and drug eruptions. Immunocompromised persons, including persons with advanced, untreated or inadequately suppressed HIV, may present with an atypical rash, including a disseminated rash that may make diagnosis more challenging.

Prevention of monkeypox and infection control practices in the home or healthcare setting are the same regardless of peoples' HIV status. Post-exposure prophylaxis (PEP) and antiviral treatments, including tecovirimat, are available for persons exposed to monkeypox or with Monkeypox virus infection. The safety and immunogenicity of JYNNEOS, a live, non-replicating viral vaccine, has been specifically established in people with HIV; however, immunogenicity among persons with HIV who have CD4 counts below 100 cells/mm³ or who are not virologically suppressed remains unknown. ACAM2000, a replicating viral vaccine, should not be given to people with HIV (regardless of immune status). Antiviral treatments for monkeypox have few interactions with antiretroviral therapy. ART and opportunistic infection prophylaxis should be continued in all people with HIV who develop monkeypox.

Recommendations and Information for Healthcare Providers on Monkeypox in Children and Adolescents

Limited pediatric data on infection with the Congo Basin clade of Monkeypox virus suggest increased risk of severe disease in children younger than 8 years of age. Rare complications of monkeypox include abscess, airway obstruction due to severe lymphadenopathy, cellulitis, corneal scarring, encephalitis, keratitis, pneumonia, and sepsis. The West African clade of Monkeypox virus involved in the current outbreak typically causes less severe disease than the Congo Basin clade.

Monkeypox virus can spread to children through contact with infectious body fluids (e.g., lesion exudates and respiratory secretions) of people or animals or through contact with fomites, as may occur in households and other close contact settings. The number of monkeypox cases among children in the United States is currently low; however, CDC acknowledges that the expanding U.S. outbreak and the possible risk for transmission in households and other settings may result in additional pediatric cases. Pediatric providers should be familiar with prevention, recognition, and testing considerations for monkeypox in children and adolescents.

Families should be counseled about preventing the spread of Monkeypox virus between children, caregivers, and household members in the home, including avoidance of contact with persons who have monkeypox, the body fluids of an infected person, and fomites (e.g., clothing, towels, bedding); wearing a well-fitting mask or respirator by the person with monkeypox and the contact (for children over 2 years of age) when interaction is unavoidable; and minimizing the number of caregivers for children with monkeypox. Particular attention should be made to keep children with monkeypox from scratching lesions or touching their eyes to prevent auto-inoculation and more severe illness. Caregivers should cover areas of broken skin with bandages to the extent possible and avoid direct skin-to-skin contact with the rash.

Children and adolescents who are close contacts of a person with monkeypox (e.g., household contact, other family member, caregiver, or friend) should be evaluated for illness and offered post-exposure prophylaxis with JYNNEOS or ACAM2000 (for children older than 12 months) or treatment when indicated. Monkeypox should be considered when children or adolescents present with signs or symptoms that could be consistent with the disease, especially if epidemiologic criteria are present. The rash of monkeypox can be confused with other rash illnesses that are commonly considered in children including varicella (chickenpox); hand, foot, and mouth disease; measles; scabies; molluscum contagiosum; herpes; allergic skin rashes and syphilis (including congenital syphilis); and drug eruptions.

Data are limited on the effectiveness of PEP for children who have been exposed to monkeypox or treatment for children with illness, and no vaccines or other products are currently licensed for monkeypox prevention or treatment in children or adolescents. However, PEP should not be withheld from children or adolescents who are otherwise eligible. Decisions about whether to offer PEP should take into account the patient's degree of exposure and the patient's individual risk of severe disease.

Prophylactic therapeutics that can be administered include vaccination, Vaccinia immune globulin, and antiviral medication. For almost all children and adolescents, vaccination is the preventive treatment that should be administered. Immune globulin or antivirals may also be considered for infants under 6 months of age, given their immature immune systems and possible decreased responses to vaccination.

Tecovirimat is currently being used as the first-line treatment for infection with Monkeypox virus, including for children and adolescents with severe disease or underlying medical conditions that may increase risk for severe disease and those with complications from monkeypox. Individual risks and benefits must be considered prior to initiating tecovirimat. Other treatments such as Vaccinia immune globulin may be considered in unusual circumstances.

In pediatric inpatient care settings, infection control procedures for children with monkeypox infection should also consider the child's age and caregiving needs; family and caregiver preferences; the extent, severity, and course of the child's illness; and risks for severe monkeypox disease in exposed caregivers (e.g., pregnancy or immunocompromising conditions).

Recommendations and Information for Healthcare Providers on Monkeypox in People who are Pregnant or Breastfeeding

Data regarding Monkeypox virus infection during pregnancy are limited. It is unknown if pregnant people are more susceptible to acquiring Monkeypox virus infection or if illness is more severe during pregnancy. Other poxviruses cause more severe infection during pregnancy. Monkeypox virus can be transmitted to the fetus during pregnancy and to the newborn by close contact during and after birth. There are few case reports of spontaneous pregnancy loss and stillbirth, preterm delivery, and neonatal monkeypox infection; the frequency and circumstances for these outcomes are unknown. Whether Monkeypox virus is present in breast milk is unknown; however, it may be transmitted through close contact during breastfeeding.

Prevention measures for monkeypox infection are similar for pregnant and non-pregnant people. Pre- or post-exposure prophylaxis should be offered to people who are pregnant or breastfeeding. When pre- or post-exposure prophylaxis by vaccination is chosen, JYNNEOS, a live, non-replicating viral vaccine, can be used. ACAM2000, a replicating viral vaccine, should not be used in people who are pregnant or breastfeeding.

During pregnancy, the cause of fever may be difficult to differentiate from other infections, such as intraamniotic infection (chorioamnionitis), until the monkeypox rash appears. Pregnant patients with rashes initially considered characteristic of dermatoses of pregnancy (e.g., polymorphic eruption of pregnancy) or of more common infections (e.g., varicella zoster or sexually transmitted infections) should be carefully evaluated for a monkeypox rash, and submission of specimens of lesions for monkeypox diagnosis should be considered, especially if the person has any epidemiologic risk factors for monkeypox infection.

While most adults with Monkeypox virus infection experience self-limiting infection and recover within 2-4 weeks, pregnant and breastfeeding people should be prioritized for medical treatment, if needed, due to the probable increased risk of severe disease during pregnancy, risk of transmission to the fetus during pregnancy or to the newborn by close contact during and after birth, and risk of severe infection in newborns. Treatment for Monkeypox virus infection should be offered to people who are pregnant or breastfeeding. The risks and benefits of treatment options should be discussed with the patient.

Recommendations for infection prevention and control of monkeypox in healthcare settings are the same for pregnant and non-pregnant patients. Newborns born to people with monkeypox should be placed in isolation, and healthcare personnel should follow infection prevention and control recommendations. Patients with monkeypox should be counseled about measures to prevent risk of transmission of Monkeypox virus to their newborn from close contact and breastfeeding.

Source: Centers for Disease Control and Prevention (U.S.) (2022). Update for Clinicians on Monkeypox in People with HIV, Children and Adolescents, and People who are Pregnant or Breastfeeding. Centers for Disease Control and Prevention. Published: July 30, 2022. DOI: CDCHAN-00472.

Immunogenicity, Safety, and Efficacy of the Vaccine H56:IC31 In Reducing the Rate of Tuberculosis Disease Recurrence In HIV-negative Adults Successfully Treated for Drug-Susceptible Pulmonary Tuberculosis: A Double-Blind, Randomised, Placebo-Controlled, Phase 2b Trial

[Posted 2/Jul/2025]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: Vaccination with H56:IC31 at treatment completion for pulmonary tuberculosis did not reduce the risk of recurrent disease. H56:IC31 was well tolerated and immunogenic but might have increased the risk of relapses by endogenous strains.

BACKGROUND: People with tuberculosis who complete treatment remain at risk of recurrent disease. The vaccine H56:IC31 has been shown to be safe and immunogenic in phase 1 and 2 studies, but whether it can reduce the risk of tuberculosis recurrence is unknown.

DETAILS: In a double-blind, randomised, placebo-controlled, phase 2b trial in South Africa (five clinical trial sites) and Tanzania (one clinical trial site), we enrolled participants aged 18-60 years, without HIV, who had completed more than 5 months (22 weeks) of treatment for drug-susceptible pulmonary tuberculosis. During trial screening (<=7 days after starting treatment), two sputum samples were obtained and frozen for later comparison to recurrent isolates by whole-genome sequencing (WGS). Eligible participants were randomly assigned (1:1; block size of four) to receive two intramuscular doses in the deltoid, 56 days apart, of H56:IC31 or placebo. After the first dose of H56:IC31 or placebo, participants were followed up until study day 421 (1 year after the second dose) and checked at each visit for tuberculosis signs and symptoms. If tuberculosis was suspected, two sputum samples were obtained: one sample was tested by automated molecular test (Xpert MTB/RIF Ultra) and sent for liquid culture; and the other sample was stored frozen for later analysis by whole-genome sequencing (WGS). At the last visit (day 421), two sputum samples were obtained from all sputum-productive participants, regardless of symptoms, to detect cases of asymptomatic tuberculosis. The primary endpoint was culture-confirmed recurrent pulmonary tuberculosis (due to relapse with the same strain, reinfection by a different strain, or indeterminate) occuring during the period starting at day 70 (14 days after the second dose) and ending on day 421 (1 year after the second dose). Vaccine efficacy against recurrent tuberculosis was derived from Cox proportional hazards models. Secondary endpoints included vaccine efficacy to prevent tuberculosis relapse or reinfection independently, as differentiated by WGS, and safety and immunogenicity outcomes (H56-specific CD4 T-cell responses and humoral anti-H56 IgG responses). Primary analysis of vaccine efficacy was based on modified intention-to-treat (mITT), in all randomly assigned participants except those with tuberculosis disease recurrence or who withdrew before day 70 (or 14 days after the second dose for those who received both doses). Safety was assessed in all randomly assigned participants who received at least one dose of vaccine or placebo. The trial was registered with ClinicalTrials.gov, NCT03512249, and is complete. 831 participants (mean age 34.7 years [SD 11.1]; 229 [28%] female and 602 [72%] male; 549 [66%] Black) were enrolled from Jan 31, 2019, to Jan 20, 2022; 415 participants were randomly assigned to receive H56:IC31 and 416 to receive placebo. Follow-up was completed by March 20, 2023 (mean follow-up duration 410.1 days [SD 82.8]). In the primary mITT analysis, recurrent tuberculosis occurred in 23 of 400 participants in the H56:IC31 group (12 relapses, eight reinfections, and three indeterminate); and in 14 of 406 in the placebo group (six relapses, seven reinfections, and one indeterminate). Vaccine efficacy for prevention of recurrence was -73.8% (95% CI -246.9 to 9.8; p=0.10). Vaccine efficacy for prevention of relapse was -116.1% (-522.2 to 16.3; p=0.11) and for prevention of reinfection was -21.1% (-245.3 to 56.5; p=0.71). 2 weeks after the planned second dose, H56:IC31 had significantly increased the frequencies of H56-specific CD4 T cells expressing interferon-γ, tumour necrosis factor, interleukin (IL)-2, or IL-17 in vaccinees (median percentage of CD4 T cells, 0.35% [IQR 0.19 to 0.57]) compared with placebo (0.11% [0.09 to 0.23]; p < 0.0001). H56-specific IgG responses were significantly higher in H56:IC31 recipients (median arbitrary units per mL, 6.84 [IQR 1.64 to 32.8]) than in placebo recipients (1.94 [1.05 to 3.86]; p < 0.0001). A greater proportion of H56:IC31 recipients had mild-to-moderate injection site reactions than placebo recipients (165 [40%] of 415 vs 78 [19%] of 416). No treatment-related serious adverse events were reported. Two participants who received H56:IC31 and six who received placebo died.

Copyright © Elsevier Ltd. All rights reserved.

Source: Borges, A. H., Russell, M., Tait, D., et al. Immunogenicity, Safety, and Efficacy of the Vaccine H56:IC31 In Reducing the Rate of Tuberculosis Disease Recurrence In HIV-negative Adults Successfully Treated for Drug-Susceptible Pulmonary Tuberculosis: A Double-Blind, Randomised, Placebo-Controlled, Phase 2b Trial. The Lancet Infectious Diseases. 2025; 25(7): 751-763. Published: July, 2025. DOI: 10.1016/S1473-3099(24)00814-4.

[Posted 6/Nov/2024]

AUDIENCE: Gastroenterology, Infectious Disease, Internal Medicine

KEY FINDINGS: The results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection.

BACKGROUND: New antiviral approaches that target multiple aspects of the HBV replication cycle to improve rates of functional cure are urgently required. HBV RNA represents a novel therapeutic target. Here, we programmed CRISPR-Cas13b endonuclease to specifically target the HBV pregenomic RNA and viral mRNAs in a novel approach to reduce HBV replication and protein expression.

DETAILS: Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pregenomic RNA. Mammalian cells transfected with replication competent wild-type HBV DNA of different genotypes, a HBV-expressing stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-BFP (blue fluorescent protein) and crRNA plasmids, and the impact on HBV replication and protein expression was measured. Wild-type HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and serum HBsAg was measured. PspCas13b mRNA and crRNA were also delivered to a HBsAg-expressing stable cell line via lipid nanoparticles and the impact on secreted HBsAg determined. The HBV-targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p <0.0001). HBV protein expression was also reduced in a HBV-expressing stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p <0.0001) in vivo. Lipid nanoparticle-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p = 0.0168) in a HBsAg-expressing stable cell line.

Copyright © Elsevier Inc. All rights reserved.

Source: McCoullough, L. C., Fareh, M., Hu, W., et al. (2024). CRISPR-Cas13b-mediated Suppression of HBV Replication and Protein Expression. Journal of Hepatology. 2024; 81(5): 794-805. Published: November, 2024. DOI: 10.1016/j.jhep.2024.05.025.

First Influenza Vaccine That Does Not Need to be Administered by a Health Care Provider

[Posted 4/Oct/2024]

AUDIENCE: Infectious Disease, Family Medicine, Nursing

On September 20, 2024, the U.S. Food and Drug Administration approved FluMist for self- or caregiver-administration. FluMist is approved for the prevention of influenza disease caused by influenza virus subtypes A and B in individuals 2 through 49 years of age. FluMist is sprayed into the nose and has been used safely and effectively for many years. It was initially approved by the FDA in 2003 for use in individuals 5 through 49 years of age, and in 2007, the FDA approved the use of FluMist to include children 2 through 5 years of age. It is the first vaccine to prevent influenza, more commonly known as the flu, that does not need to be administered by a health care provider

"Today's approval of the first influenza vaccine for self- or caregiver-administration provides a new option for receiving a safe and effective seasonal influenza vaccine potentially with greater convenience, flexibility and accessibility for individuals and families," said Peter Marks, M.D., Ph.D., director of the FDA's Center for Biologics Evaluation and Research. "Getting vaccinated each year is the best way to prevent influenza, which causes illness in a substantial proportion of the U.S. population every year and may result in serious complications, including hospitalization and death. This approval adds another option for vaccination against influenza disease and demonstrates the FDA's commitment to advancing public health."

The flu is a common and contagious respiratory disease that is caused by influenza viruses that typically circulate during the fall and winter in the U.S. It can cause mild to severe illness with a range of symptoms that usually appear suddenly, such as body aches, fever, coughing, sore throat, tiredness and a stuffy or runny nose. Flu can be life-threatening and cause serious complications that can lead to hospitalization or death, particularly in high-risk groups such as the elderly, young children and people with certain chronic medical conditions. Each flu season is different and the health impacts can be substantial and vary widely from season to season, with some flu seasons being worse than others. According to the U.S. Centers for Disease Control and Prevention, flu has resulted in about 9.3 million to 41 million illnesses, 100,000 to 710,000 hospitalizations and 4,900 to 51,000 deaths annually between 2010 and 2023. Numerous FDA-approved vaccines are available each flu season to prevent influenza.

FluMist contains a weakened form of live influenza virus strains and is sprayed in the nose. A prescription is still required to receive FluMist. There are now two approved options for receiving FluMist. The vaccine may be administered by a health care provider in a health care setting (including a pharmacy) or it may be administered by the vaccine recipient or a caregiver who is 18 years of age or older.

The most commonly reported side effects of FluMist are fever over 100°F in children 2 through 6 years of age, runny nose and nasal congestion in individuals 2 through 49 years of age and a sore throat in adults 18 through 49 years of age.

For those interested in self- or caregiver-administration, the vaccine manufacturer plans to make the vaccine available through a third-party online pharmacy. Those who choose this option will complete a screening and eligibility assessment when they order FluMist. The third-party pharmacy determines eligibility based on the completed screening and, if it is determined that the intended vaccine recipient is eligible, the pharmacy writes the prescription and ships the vaccine to the address provided by the individual who placed the order. The vaccine can then be administered to the prescribed household member(s) at their convenience. A caregiver should administer FluMist to individuals 2 through 17 years of age, as individuals in this age group should not self-administer the vaccine.

A study was conducted with vaccine recipients and caregivers to evaluate whether the instructions for use were appropriately designed so that recipients and caregivers could safely and effectively use the vaccine.

Vaccine recipients and caregivers who administer FluMist will be sent the vaccine, the Prescribing Information, Information for Patients and their Caregivers and Instructions for Use. The Instructions for Use provides detailed instructions for storage, administration and disposal of FluMist.

The FDA granted this approval of FluMist (Influenza Vaccine Live, Intranasal) to MedImmune LLC.

Source: FDA Approves Nasal Spray Influenza Vaccine for Self- or Caregiver-Administration. FDA. 2024; Published: September, 2024. DOI: FDA.

A Phase 2C, Open-Label, Multicentre, Partially Randomised Controlled Trial

[Posted 27/Aug/2024]

AUDIENCE: Infectious Disease, Family Medicine

KEY FINDINGS: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments.

BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB.

DETAILS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2.93 (95% CI 2.17-3.96; p<0.0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]).

Copyright © The Author(s). Published by Elsevier Ltd. All rights reserved.

Source: Cevik, M., Thompson, L. C., Upton, C., et al. (2024). Bedaquiline-Pretomanid-Moxifloxacin-Pyrazinamide for Drug-Sensitive and Drug-Resistant Pulmonary Tuberculosis Treatment: A Phase 2C, Open-Label, Multicentre, Partially Randomised Controlled Trial. The Lancet Infectious Diseases. 2024; 24(9): 1003-1014. Published: September, 2024. DOI: 10.1016/S1473-3099(24)00223-8.

A Phase 1, Double-Blind Trial

[Posted 13/Aug/2024]

AUDIENCE: Infectious Disease, Nursing, Ob/Gyn

KEY FINDINGS: CTH522, adjuvanted with CAF01 or CAF09b, is safe and immunogenic, with 85 μg CTH522-CAF01 inducing robust serum IgG binding titres. Intradermal vaccination conferred systemic IgG neutralisation breadth, and topical ocular administration increased ocular IgA formation. These findings indicate CTH522 vaccine regimens against ocular trachoma and urogenital chlamydia for testing in phase 2, clinical trials.

BACKGROUND: There is no vaccine against the major global pathogen Chlamydia trachomatis; its different serovars cause trachoma in the eye or chlamydia in the genital tract. Authors did a clinical trial administering CTH522, a recombinant version of the C trachomatis major outer membrane molecule, in different dose concentrations with and without adjuvant, to establish its safety and immunogenicity when administered intramuscularly, intradermally, and topically into the eye, in prime-boost regimens.

DETAILS: CHLM-02 was a phase 1, double-blind, randomised, placebo-controlled trial at the National Institute for Health Research Imperial Clinical Research Facility, London, UK. Participants were healthy men and non-pregnant women aged 18-45 years, without pre-existing C trachomatis genital infection. Participants were assigned into six groups by the electronic database in a pre-prepared randomisation list (A-F). Participants were randomly assigned (1:1:1:1:1) to each of the groups A-E (12 participants each) and 6 were randomly assigned to group F. Investigators were masked to treatment allocation. Groups A-E received investigational medicinal product and group F received placebo only. Two liposomal adjuvants were compared, CAF01 and CAF09b. The groups were intramuscular 85 µg CTH522-CAF01, or placebo on day 0 and two boosters or placebo at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (A); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional topical ocular administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (B); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional intradermal administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (C); intramuscular 15 µg CTH522-CAF01, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (D); intramuscular 85 µg CTH522-CAF09b, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (E); intramuscular placebo (F). The primary outcome was safety; the secondary outcome (humoral immunogenicity) was the percentage of trial participants achieving anti-CTH522 IgG seroconversion, defined as four-fold and ten-fold increase over baseline concentrations. Analyses were done as intention to treat and as per protocol. The trial is registered with ClinicalTrials.gov, NCT03926728, and is complete. Between Feb 17, 2020 and Feb 22, 2022, of 154 participants screened, 65 were randomly assigned, and 60 completed the trial (34 [52%] of 65 women, 46 [71%] of 65 White, mean age 26.8 years). No serious adverse events occurred but one participant in group A2 discontinued dosing after having self-limiting adverse events after both placebo and investigational medicinal product doses. Study procedures were otherwise well tolerated; the majority of adverse events were mild to moderate, with only seven (1%) of 865 reported as grade 3 (severe). There was 100% four-fold seroconversion rate by day 42 in the active groups (A-E) and no seroconversion in the placebo group. Serum IgG anti-CTH522 titres were higher after 85 µg CTH522-CAF01 than 15 µg, although not significantly (intention-to-treat median IgG titre ratio groups A-C:D=5.6; p=0.062), with no difference after three injections of 85 µg CTH522-CAF01 compared with CTH522-CAF09b (group E). Intradermal CTH522 (group C) induced high titres of serum IgG anti-CTH522 neutralising antibodies against serovars B (trachoma) and D (urogenital). Topical ocular CTH522 (group B) at day 28 and 112 induced higher total ocular IgA compared with baseline (p0.001). Participants in all active vaccine groups, particularly groups B and E, developed cell mediated immune responses against CTH522.

Copyright © Elsevier Ltd. All rights reserved.

Source: Pollock, K. M., Borges, A. H., Cheeseman, H. M., et al. (2024). An Investigation of Trachoma Vaccine Regimens by the Chlamydia Vaccine CTH522 Administered With Cationic Liposomes in Healthy Adults (CHLM-02): A Phase 1, Double-Blind Trial. The Lancet. 2024; 24(8): 829-844. Published: August, 2024. DOI: 10.1016/S1473-3099(24)00147-6.