Virus World

Back in January, Moderna set a planned mpox vaccine on the back burner as the immediate outbreak waned, but now the shot has slid into the priority lane, with entry to the clinic likely a “month or | Back in January, Moderna set a planned mpox vaccine on the back burner as the immediate outbreak waned, but now the shot has slid into the priority lane, with entry to the clinic likely a “month or so” away, according to a top vaccine developer and strategist at the company. Moderna is set to launch a phase 1/2 trial of the shot this summer, Hamilton Bennett, senior director of vaccine access and partnerships at Moderna, said in an interview at the the BIO International Convention. The company had previously teased launching human trials sometime this year. 

Bennett said the goal is to build a preclinical data package that shows efficacy across orthopoxviruses, which include mpox and smallpox, and then generate "robust" phase 1/2 data to inform dose selection and eventually licensure. She added that the company has met with the U.S. mpox response team a couple of times to say, “this is where we are, these are the barriers that we're seeing.”  “They've been incredibly helpful in helping us get access to samples and people and information,” she said. Moderna CEO Stéphane Bancel told Fierce Biotech in January that developing a mpox vaccine was not a high priority as development pressed ahead on more than a dozen unique assets beyond the COVID vaccine that helped make the company a household name. Bennett clarified that he was speaking relative to Moderna’s urgency to develop a COVID-19 vaccine during the pandemic.  “I think when Stéphane says it's not a priority, it is not a COVID-like priority,” she said. 

The upcoming trials are just the latest example of the swiftness of Moderna's mRNA platform. The company announced in May 2022 that preclinical work would begin on an mpox vaccine. But no update had been made on the progress prior to Bancel's comments at the beginning of the year.  For Bennett, the development of the shot means more than just the potential for a new product; it’s an opportunity to flex her muscles leading the company’s public health portfolio, a position she’s pivoted to since helping lead development and dissemination of the COVID shot. That new role broadly puts her in charge of coordinating with developing nations to help scale up vaccine-related economic infrastructure and ensuring that Moderna is accountable and its products are available to those nations. Bennett said that mpox is a “perfect example” of some of the barriers the company will face as it develops these products, in part because, as of now, funding for an mpox vaccine is really for a smallpox vaccine. At a grander level, mpox represents a virus that only gained national attention when people outside of Africa began to be infected. Bennett doesn’t want Moderna to be caught on its back foot when addressing diseases of significance, even if they aren’t affecting high-income countries. “Our portfolio in global health is designed to allow those associations to happen because they're not something where we can pick up the phone when the clock starts,” she said. “We need to build those relationships now.” 

Monkeypox has infected more than 77,000 people in more than 100 countries worldwide, and—similar to COVID-19—mutations have enabled the virus to grow stronger and smarter, evading antiviral drugs and vaccines in its mission to infect more people. Now, a team of researchers at the University of Missouri have identified the specific mutations in the monkeypox virus that contribute to its continued infectiousness. The findings could lead to several outcomes: modified versions of existing drugs used to treat people suffering from monkeypox or the development of new drugs that account for the current mutations to increase their effectiveness at reducing symptoms and the spread of the virus. Kamlendra Singh, a professor in the MU College of Veterinary Medicine and Christopher S. Bond Life Sciences Center principal investigator, collaborated with Shrikesh Sachdev, Shree Lekha Kandasamy and Hickman High School student Saathvik Kannan, to analyze the DNA sequences of more 200 strains of monkeypox virus spanning multiple decades, from 1965, when the virus first started spreading, to outbreaks in the early 2000s and again in 2022. "By doing a temporal analysis, we were able to see how the virus has evolved over time, and a key finding was the virus is now accumulating mutations specifically where drugs and antibodies from vaccines are supposed to bind," Sachdev said. "So, the virus is getting smarter, it is able to avoid being targeted by drugs or antibodies from our body's immune response and continue to spread to more people."

Needles in a haystack

Singh has been studying virology and DNA genome replication for nearly 30 years. He said the homology, or structure, of the monkeypox virus is very similar to the vaccinia virus, which has been used as a vaccine to treat smallpox. This enabled Singh and his collaborators to create an accurate, 3D computer model of the monkeypox virus proteins and identify both where the specific mutations are located and what their functions are in contributing to the virus becoming so infectious recently. "Our focus is on looking at the specific genes involved in copying the virus genome, and monkeypox is a huge virus with approximately 200,000 DNA bases in the genome," Singh said. "The DNA genome for monkeypox is converted into nearly 200 proteins, so it comes with all the 'armor' it needs to replicate, divide and continue to infect others. Viruses will make billions of copies of itself and only the fittest will survive, as the mutations help them adapt and continue to spread."  Kannan and Kandasamy examined five specific proteins while analyzing the monkeypox virus strains: DNA polymerase, DNA helicase, bridging protein A22R, DNA glycosylase and G9R. "When they sent me the data, I saw that the mutations were occurring at critical points impacting DNA genome binding, as well as where drugs and vaccine-induced antibodies are supposed to bind," Singh said. "These factors are surely contributing to the virus' increased infectivity. This work is important because the first step toward solving a problem is identifying where the problem is specifically occurring in the first place, and it is a team effort."

The evolution of viruses

Researchers continue to question how the monkeypox virus has evolved over time. The efficacy of current CDC-approved drugs to treat monkeypox have been suboptimal, likely because they were originally developed to treat HIV and herpes but have since received emergency use authorization in an attempt to control the recent monkeypox outbreak. "One hypothesis is when patients were being treated for HIV and herpes with these drugs, they may have also been infected with monkeypox without knowing, and the monkeypox virus got smarter and mutated to evade the drugs," Singh said. "Another hypothesis is the monkeypox virus may be hijacking proteins we have in our bodies and using them to become more infectious and pathogenic." Singh and Kannan have been collaborating since the COVID-19 pandemic began in 2020, identifying the specific mutations causing COVID-19 variants, including Delta and Omicron. Kannan was recently recognized by the United Nations for supporting their 'Sustainable Development Goals,' which help tackle the world's greatest challenges. "I could not have done this research without my team members, and our efforts have helped scientists and drug developers assist with these virus outbreaks, so it is rewarding to be a part of it," Singh said. "Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak" was recently published in Journal of Autoimmunity. Co-authors on the study include Shrikesh Sachdev, Athreya Reddy, Shree Lekha Kandasamy, Siddappa Byrareddy, Saathvik Kannan and Christian Lorson.

Research cited published in Journal of Autoimmunity (Dec. 22, 2022):

https://doi.org/10.1016/j.jaut.2022.102928 

In the recent Morbidity and Mortality Weekly Report (MMWR) published by the Centers for Disease Control and Prevention (CDC), researchers reported on JYNNEOS vaccine effectiveness (VE) against Mpox infections among New York (NY) residents in 2022. Bavarian Nordic’s JYNNEOS (Modified Vaccinia Ankara) vaccine was used in the state- and nation-wide vaccination campaigns during the 2022 Mpox outbreak, which primarily affected gays, bisexuals, and males who had sex with males (MSM). As a result, health authorities prioritized postexposure prophylaxis (PEP) and vaccinating high-risk individuals (mainly MSM). However, data on JYNNEOS VE from controlled trials are limited.

About the report

In the present report, researchers presented JYNNEOS VE in preventing Mpox infections among NY residents during 2022. The team compared JYNNEOS vaccination results among adult males with laboratory-verified Mpox (case-patients) diagnosed between 24 July and 31 October 2022, in New York, to those among control individuals diagnosed with primary syphilis or rectal gonorrhea and prior history of sexual intercourse with males without Mpox infection. Surveillance data were systematically obtained for the analysis. The team matched cases and controls to the vaccination system records of the state. Logistic regression modeling was performed to calculate the odds ratios (OR), which were used along with the number of JYNNEOS vaccination doses received to estimate VE. The data were adjusted for age, ethnicity, race, a residential region within New York but outside of New York City, and the Mpox diagnosis week. The status of JYNNEOS vaccination was classified into the following groups: an unvaccinated group (zero JYNNEOS vaccine doses received); vaccinated for Mpox or sexually transmitted infections (STIs) with specimens obtained within two weeks of initial vaccine administration; vaccinated with STI specimens obtained after two or more weeks of the initial vaccination; and vaccinated with STI specimens obtained following the subsequent vaccination. Reports were assessed by population health staff members and entered into the Communicable Disease Electronic Surveillance System (CDESS). One-dose, two-dose, and combined estimates of JYNNEOS vaccine effectiveness were obtained.

Results

Between 2 June and 31 December 2022, the NYSDOH recorded 375 Mpox cases, and the NYSIIS recorded 27,385.0 vaccine doses administered, of which 61% (n=16,769) and 39% (n=10,616) were the first and second doses, respectively. The case counts were highest in the middle of August, five weeks following the JYNNEOS immunization campaign launch. Between 24 July and 31 October, 252 cases and 255 controls (80 and 175 with primary-type syphilis and rectal gonorrhea, respectively) satisfied the eligibility criteria and had similar ages. Hispanics were more common among cases than controls (44% versus 19%, respectively), and more cases  (69%) than controls (36%) resided in urban areas outside New York City. The majority (91%) of participants (n=220) were unvaccinated, and 9.0% of cases (n=22) were JYNNEOS vaccinees, among whom 10 individuals (4.0%), 10 individuals (4.0%), and two individuals (1.0%) had received one dose <2.0 weeks prior, one dose ≥2.0 weeks prior, and two doses, respectively. Among controls, 51 (20%) were JYNNEOS vaccinees, including 42 individuals (17%) who were diagnosed with an STI ≥2.0 weeks after receiving the initial dose (9.0%, 23 individuals) or both doses (7.5%, 19 individuals). The adjusted one-dose, two-dose, and combined JYNNEOS VE estimates were 68%, 89%, and 76%, respectively. JYNEEOS VE observed in less than two weeks of receiving the initial dose was non-significant, probably due to the inclusion of PEP recipients and individuals with Mpox exposure after vaccination but before developing protective immunity.

Multiple sensitivity analyses were performed to assess the robustness of the study findings. The initial analyses, excluding males aged ≥50.0 years who may have been administered smallpox vaccines before the termination of regular non-military US vaccinations in 1972, yielded similar results. The second analysis comprised 71.0 control individuals diagnosed with secondary syphilis and yielded a single-dose or double-dose VE of 65.0%. Among controls, 84% (n=213) underwent testing due to the presence of symptoms (41%, 88 individuals), partner referrals (9.0%, 19 individuals), screening purposes (48%, 103 individuals), or other reasons (1.40%, three individuals). The third sensitivity analysis, including only control individuals undergoing testing due to referrals or symptoms, yielded a one-dose or two-dose VE estimate of 64.0%. The fourth sensitivity analysis included the findings of only individuals with known ethnicity and race estimates, yielded single-dose or double-dose VE estimates of 81.0%. The lower estimated VE obtained by analyzing secondary syphilis patients may reflect control individuals with different clinical presentations or more remote risk behaviors. Lower VE obtained by limiting the control group to individuals undergoing testing due to symptoms or referrals may reflect the intended elimination of low-risk individuals seeking care or the inadvertent elimination of high-risk individuals accessing Mpox screening frequently. Based on the findings, the adjusted combined one-dose (administered ≥2.0 weeks prior) or two-dose JYNNEOS vaccine effectiveness was 76%. The findings underpin the advocacy of two-dose JYNNEOS vaccination regimens to prevent Mpox, following CDC and NY State Department of Health (NYSDOH) recommendations. The vaccine may be incorporated into broader sexual health programs.

Cited study published (May 19, 2023) in MMWR:

http://dx.doi.org/10.15585/mmwr.mm7220a4

The Biden administration has proposed using a less common injection method that would allow a single dose of the monkeypox vaccine to be split into five. As the monkeypox virus continues to spread in the United States, the Biden administration has adopted a strategy of vaccine-splitting to stretch the nation’s limited supply. A method known as intradermal vaccination allows a single-use vial to be split into five injections. Bavarian Nordic makes Jynneos, the only monkeypox-specific vaccine approved in the United States. It was initially approved by the Food and Drug Administration for a single 0.5 milliliter subcutaneous injection, followed by a second 0.5 milliliter dose four weeks later....