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Sundararaman is an attending physician with the Division of Infectious Diseases at the Children’s Hospital of Philadelphia (CHOP).

Sesh Sundararaman, MD, PhD, discusses his findings and how this approach can be triggered to minimize undesirable treatment features and open the door to newer treatment possibilities.  

How a Prodrug Approach May Aid In Antimalarial Development

Along with a 1 reported case in Massachusetts, the

New Hampshire Department of Health and Human Services (DHHS) has confirmed a person infected with eastern equine encephalitis (EEE) has died. The public health agency said the person was hospitalized due to severe central nervous system disease. The last reported human EEEV infection in New Hampshire was in 2014, when DHHS identified 3 human infections, including 2 fatalities. In the same statement, DHHS mentions there has been 1 confirmed case in Vermont this summer.

On August 16, the Massachusetts Department of Public Health (MDPH) released a statement discussing the confirmation of the first human case of EEE in the state this year. The confirmed case was discovered in an 80 year old man who was exposed to the vector borne disease in Worcester County. As a result, the risk level in the local communities of Douglas, Oxford, Sutton, and Webster has been raised to critical, and in Dudley, Northbridge, and Uxbridge the risk is increased to high.

Additionally, the neighboring communities of Auburn, Charlton, Grafton, Leicester, Mendon, Millbury, Millville, Southbridge, and Upton are now considered at moderate risk according to MDPH.

“This is the first time we have seen a person infected with EEE in Massachusetts since 2020,” Public Health Commissioner Robbie Goldstein, MD, PhD, said in a statement. “EEE is a rare but serious disease and a public health concern. We want to remind residents of the need to protect themselves from mosquito bites, especially in areas of the state where we are seeing EEE activity.

Though very rare, EEE is serious and a potentially fatal disease that can affect people of all ages. EEE is generally spread to humans through the bite of an infected mosquito. There were 12 human cases of EEE in Massachusetts in 2019 with 6 deaths, and 5 human cases with 1 death in 2020. There were no human cases of EEE in Massachusetts in 2021, 2022, or 2023.

EEE has a fatality rate of 33% to 70%, with most deaths occurring 2–10 days after the onset of symptoms.

In addition to a high mortality rate, long-term physical and mental complications, including permanent neurological deficits have been identified in many people who survive EEE.

Plymouth is approximately 40 miles south of Boston along the coast, and Worcester County is in the middle of the state, so the 2 areas are not in close proximity, but due to the elevated risk locally, the town of Plymouth decided to take action in response to outdoor parks. As of last Friday, all town public parks and fields are close daily from dusk until dawn.

“As Mass DPH has now elevated Plymouth’s EEE risk status to high, it is important to take extra precautions when outdoors and follow state and local health guidelines to avoid unnecessary risk to exposure to EEE. The health and safety of our community, residents, and visitors remain our priority,” Plymouth’s Commissioner of Health and Human Services, Michelle Bratti, said in a statement.

According to the Centers for Disease Control and Prevention (CDC) most people who are infected with the virus do not develop symptoms; however, for those that do, the date from the bite to the onset of the illness is 4 to 10 days. EEE can also result in fever or neurologic disease. The type of illness will depend on the age of the person and other factors. Those who are infected can develop meningitis.

There are no FDA-approved treatments for EEE and for patients who develop severe cases, they can be hospitalized to receive supportive treatment.

Over the weekend, MDPH detailed plans of spraying for mosquitos including aerially in areas of Plymouth County, and truck-mounted spraying in parts of Worcester County. As of Saturday, 10 communities in Massachusetts were raised to high or critical risk for EEE virus.

“The risk from EEE is high in parts of Plymouth County and critical in parts of Worcester County,” State Epidemiologist Catherine M. Brown, DVM, said in a statement. “In addition to recommending that people use mosquito repellent with an EPA-registered active ingredient and clothing to reduce exposed skin, we also recommend that evening outdoor events be rescheduled to avoid the hours between dusk and dawn. The mosquitoes most likely to spread EEE are most active during the dusk to dawn hours.”

There are preventative strategies to avoid EEE, and the MDPH has listed such measures 

For those who live in Massachusetts and want more information on EEE, it can be found 

 or by calling the DPH Division of Epidemiology at 617-983-6800.

1.NH DHHS Identifies Person Infected with Eastern Equine Encephalitis Virus in New Hampshire.The New Hampshire Department of Health and Human Services. August 27, 2024. Accessed August 28, 2024.
https://www.dhhs.nh.gov/news-and-media/nh-dhhs-identifies-person-infected-eastern-equine-encephalitis-virus-new-hampshire
2. State health officials announce season’s first human case of Eastern Equine Encephalitis in Massachusetts. MDPH. August 16, 2024. Accessed August 27, 2024.
https://www.mass.gov/news/state-health-officials-announce-seasons-first-human-case-of-eastern-equine-encephalitis-in-massachusetts
3.Plymouth to Close all Public Parks and Fields from Dusk to Dawn. Town of Plymouth. August 23, 2024. Accessed August 27, 2024. PDF.
4. Eastern Equine Encephalitis: Symptoms, Diagnosis, and Treatment. CDC. May 15, 2024. Accessed August 27, 2024.
https://www.cdc.gov/eastern-equine-encephalitis/symptoms-diagnosis-treatment/index.html
5. State officials announce plans to spray for mosquitoes in sections of Worcester and Plymouth counties due to EEE. MDPH. August 24, 2024. Accessed August 27, 2024. 
https://www.mass.gov/news/state-officials-announce-plans-to-spray-for-mosquitoes-in-sections-of-worcester-and-plymouth-counties-due-to-eee



The town of Plymouth decided to prohibit people from using the parks from dusk to dawn due to concerns over eastern equine encephalitis after a man contracted the rare disease in the state.

Concerns Over Mosquito-Borne Illness Causes Massachusetts Town to Create Curfew for Parks, Spraying in Counties

Antimalarial treatments continue to face resistance in both Asia and Africa—2 continents devastated by this vector-borne disease. Sesh Sundararaman, MD, PhD, an attending physician with the Division of Infectious Diseases at the Children’s Hospital of Philadelphia (CHOP), points out that not only is resistance growing with existing artemisinin-based combination therapies (ACTs), but a particular strain can be much more severe.

“We know that it's occurring in a few countries in Africa. It's a big risk because the majority of cases of falciparum malaria, which is the deadliest form of malaria, occur in Sub-Saharan Africa,” Sundararaman said. “So if we lose our ability to treat patients with those drugs, we will see an increase in mortality and morbidity.”

Developing new therapies can be challenging because they are either poorly absorbed in the gastrointestinal tract or absorbed and eliminated from the body too rapidly. One potential strategy for drug development is the use of prodrugs, which are designed to improve a drug’s ability to be absorbed or to reach its target. Prodrugs work like a Trojan horse, offering a more targeted attack against infections and diseases once they reach the appropriate tissues or cells. However, prodrugs are inactive and must be activated, typically by an enzyme, to achieve their desired effect.

Sundararaman and colleagues at CHOP studied how antimalarial prodrugs are activated, with the goal of identifying a way to more effectively treat malaria.

“Prodrugging is really a way to help our drugs get to where they need to go,” Sundararaman said. “And prodrugs are actually used very commonly in the pharmaceutical industry. The main reason is that we have drugs that may have properties making them poorly absorbed. One of the things chemists can do is attach these prodrug groups that mask those properties, making a poorly absorbed drug better absorbed.”

Sundararaman and his team found that a human enzyme, acylpeptide hydrolase (APEH), is the major activating enzyme for multiple antimalarial prodrugs known as lipophilic ester prodrugs. The APEH enzyme is normally found in red blood cells. However, in the case of malaria, the enzyme is taken into the parasite’s cytoplasm, where APEH retains its activity. The researchers’ findings suggest that APEH activates antimalarial prodrugs within the parasite, greatly increasing the potency of the lipophilic ester prodrugs.

“It seems that at least 2 different pivaloxymethyl (POM) prodrugs—the 'POM' group being the focus of this paper—are activated by the enzyme, which suggests that other prodrugs could also be activated by the same human enzyme that is taken up by the parasite,” Sundararaman said.

Their findings were recently published in the journal 

Proceedings of the National Academy of Sciences

1.Children’s Hospital of Philadelphia Researchers Use a “Trojan Horse” Approach to Develop New Antimalarial Drugs. CHOP. March 5, 2025. Accessed March 21, 2025.
https://www.chop.edu/news/childrens-hospital-philadelphia-researchers-use-trojan-horse-approach-develop-new-antimalarial



The Miami-based Jackson Health System, a nonprofit academic medical organization, saw significant increases in the fungal infection 

 every year over a 5-year period (2019–2023).¹ They experienced their largest percentage increase from 2019 to 2020, going from 5 cases in 2019 to 29 cases in 2020. This represents a 590% increase. The health system saw increases every year thereafter, with 71 cases in 2021 (a 145% increase compared to 2020), 107 cases in 2022 (a 51% increase compared to 2021), and 115 cases in 2023 (a 7% increase compared to 2022).¹

This was a retrospective observational study, and its results were published in the 

. The investigators included clinical cultures with 

 but did not include surveillance cultures. Specimens were processed through routine methods, and identification was performed using mass spectrometry. Whole-genome sequencing was performed on select specimens.¹

The predominant source was blood cultures, but the investigators noted that specimens originating from soft tissue and bone infections saw a large increase in 2022 and 2023.¹

“The volumes of clinical cultures with 

 have rapidly increased, accompanied by an expansion in the sources of infection,” the investigators wrote.¹

They also noted that all the sequenced isolates belonged to clade III (South African) and were found to be resistant to fluconazole but susceptible to echinocandins and amphotericin B.¹

 continues to increase nationwide. The most recent year of surveillance is 2023, and the Centers for Disease Control and Prevention (CDC) reported 4,514 cases of 

 in the US during that year. The agency also noted that the number of clinical cases has continued to increase since the first US case was reported in 2016. The CDC emphasizes that case numbers and trends vary by state.²

 often appears in clusters or small outbreaks within hospitals or long-term care facilities. Three states—Florida (568), California (642), and Nevada (599)—reported the highest number of cases nationwide, followed by Texas (492), Illinois (477), and New York (413). Several Mountain and New England states reported no new cases in 2023.

The CDC explains that state and local health departments submit clinical case count data to the agency. The agency also notes that case counts on some state and local health department websites may differ from federal numbers. For example, the CDC’s webpage currently shows data for clinical cases only, while some states report both clinical and screening cases.

“Differences in counts may also occur because of differences in how cases are counted (such as by case, specimen, or patient; reported date versus specimen collection date; or where the patient lives versus where the patient's sample was collected),” the CDC writes on its website.

1. Rosa R, Baptista RP, Tran TT, et al. Changing Trends in the Sources and Volumes of Clinical Cultures with Candida auris at a Large Health System, 2019-2023. 

. Published online March 17, 2025. doi:10.1016/j.ajic.2025.03.013
2. Tracking C. auris. CDC. December 9, 2024. Accessed March 21, 2025.
https://www.cdc.gov/candida-auris/tracking-c-auris/index.html?2023=2023

Examined over a 5-year period, the Jackson Health System in Florida reported large volumes of positive cultures for the fungal infection every year and that infection sources expanded over time.

Large Hospital System Experiences Significant Increases in Candida auris 

David Berman, MD, PhD, discusses promising signs of dose-dependent viral control and reduction in active HIV reservoir in Phase 1/2 STRIVE trial data

Title: Immunocore Reports 2/5 Participants Achieve Viral Control and HIV Reservoir Reduction Across 3 Dose Cohorts of IMC-M113V

Immunocore Holdings plc presented early findings from the multiple ascending dose (MAD) phase of its Phase 1/2 STRIVE trial for IMC-M113V at CROI 2025 in San Francisco, California. The data suggest that IMC-M113V, a T-cell receptor bispecific therapy, is well tolerated and demonstrates signs of dose-dependent viral control after antiretroviral treatment (ART) interruption.

The trial included 16 participants living with HIV (PLWH) who were stable on ART. David Berman, MD, PhD, executive vice president of research and development at Immunocore, explained the significance of the study, stating, “Our platform is essentially, we create these off-the-shelf, soluble bispecific proteins, where you have a targeting end to target a specific cell, and then the other end is an effector, which brings T-cells close to the target cell, so close that it actually can kill the target cell. So it acts as a bridge.”

No serious adverse events were observed, and mild cytokine release syndrome (CRS) was noted in some participants at higher doses. The highest dose cohort (300 mcg) showed a dose-dependent increase in T-cell-derived cytokines. “With our cancer programs, we see evidence that you're activating T-cells. So when T-cells get activated, you see cytokines being released in the blood, and that leads to something called cytokine release syndrome. So it's fully expected, and essentially that is typically begins with fever,” Berman explained. “Now with repeated dosing, it doesn't appear to be any other adverse event, so it is very well tolerated.”

Three participants showed delayed viral rebound and subsequent viral control during ART interruption. Viral load in these individuals decreased to approximately 200 copies/mL, a result not commonly seen in untreated PLWH. The trial’s aim is to assess IMC-M113V’s ability to reduce the HIV reservoir and control viral replication after ART interruption. Berman commented, “What we saw, quite remarkably, is a dose-dependent evidence of antiviral reduction, and that's manifest as three of these people living with HIV during the ATI had an increase in their virus initially, and then it seems like the immune system was activated and the virus came under control, and the virus went back down to around 200 copies per million.”

The initial results also show a reduction in CD4+ T-cell-associated HIV Gag RNA in some participants, suggesting a reduction in the active viral reservoir. Berman explained the importance of targeting the viral reservoir, “The viral reservoir, as you point out, was the first measure. And there, it's important to remember that a majority of the viral and the analog I give is the iceberg. If you think of the iceberg, only the tip of the iceberg above the water, the tip of the viral reservoir will actually produce replication competent virus.”

Preliminary data also indicate a trend toward reduced intact HIV DNA in patients treated at the two highest doses. IMC-M113V works by targeting an HLA-A*02:01-Gag complex on HIV-infected cells, using an anti-CD3 effector to recruit T-cells that destroy HIV-infected CD4+ cells. Berman elaborated on how the therapy targets HIV, stating, “We identified a protein in HIV called gag that is chopped up inside the cell, and small peptides are presented on the surface by HLA, and we developed the targeting end of the bispecific to recognize that gag peptide.”

The trial is continuing with higher doses being evaluated, and additional expansion cohorts are planned. Berman emphasized that while the results are promising, further investigation is needed: “We need to continue dose escalating, and then we can, you know, correlate that with clinical outcome.”

The next steps for the treatment involve evaluating the antiviral activity of IMC-M113V in larger cohorts, focusing on correlating the reduction in the viral reservoir with clinical outcomes. Berman noted, “The immediate next steps for us is to continue dose escalating, because if we can, it’s very well tolerated with higher doses, we may even see further reductions. And then we would want to look at correlations between the reservoir reduction and antiviral activity.”

As the trial continues, Immunocore is working to determine whether the antiviral activity can be sustained beyond 12 weeks, with the ultimate goal of achieving a functional cure. “The goal here is functional cure. It's not a 12-week interruption of the treatment,” Berman said. “We wanted to go to the harder population, because you can see a signal. So everyone in our trial started ART later, they're less likely to spontaneously control."

Immunocore Holdings plc. Immunocore presents initial multiple ascending dose data for HIV functional cure candidate in an oral presentation at CROI 2025. 

. March 10, 2025. Accessed March 17, 2025. https://www.immunocore.com/investors/news/press-releases/detail/112/immunocore-presents-initial-multiple-ascending-dose-data-for-hiv-functional-cure-candidate-in-an-oral-presentation-at-croi-2025

David Berman, MD, PhD, discusses signs of dose-dependent viral control and reduction in active HIV reservoir in Phase 1/2 STRIVE trial data.


Conferences

Immunocore Reports Some PWH Achieve Viral Control and Dose-Dependent Active HIV Reservoir Reduction in IMC-M113V Trial

Colleen Kelley, MD, MPH, offers some insights on where we are today with the state of HIV prevention including  PrEP and PEP, as well as why HIV vaccines are challenging to develop. 

Expanding PrEP Options and the Role of  Broadly Neutralizing Antibodies in Vaccine Development 

Here is the first in a news series on the state of HIV today including prevention, funding, and newer modalities.



HIV prevention in the form of pre-exposure prophylaxis (PrEP) continues to be a highly effective method of reducing the risk of contracting HIV. According to the Centers for Disease Control and Prevention (CDC), PrEP reduces the risk of getting HIV from sex by about 99%, when taken as prescribed.

CDC says there is less information about how effective PrEP pills are among people who inject drugs; however, it is reported that PrEP pills reduce the risk of getting HIV by at least 74% when taken as prescribed. Currently, PrEP injectables are not recommended for people who inject drugs.


One of the more exciting areas within PrEP is long-acting injectables. This modality is giving individuals new options to protect against infection. At this week’s CROI, investigators presented new data on these modalities for FDA approved and developmental PrEP. For example, ViiV Healthcare reported new data the 

long-acting injectable cabotegravir (Apretude) 

demonstrating its effectiveness in 3 years of real-world data. Right now this is the only long-acting injectable that is FDA approved.

Additionally, the investigational long-acting injectable, lenacapavir, has shown high efficacy in phase 3 trials for PrEP and has a PDUFA date for June 19.



Gilead's Once-Yearly Lenacapavir Formulations Show Sustained Efficacy for HIV PrEP in Phase 1 Study



“Long acting injectables are a tremendous advancement, both for HIV prevention and treatment. So with respect to HIV prevention, we know that taking a pill every single day for the duration of the time where you may be exposed to HIV can be difficult for a lot of people,” said Colleen Kelley, MD, MPH, professor, Department of Medicine, Emory University School of Medicine. “We know that about half of people who start oral daily oral PrEP, stop it within the first year of taking it. And so what these long-acting injectables offer is the ability to have excellent HIV prevention without having to think about it, without having to take that pill every single day…and when you take daily oral adherence out of the equation, that's where we see these amazing efficacy results.” 


One area that is not discussed very often is post-exposure prophylaxis (PEP). Kelley says there are 3 challenges around it including the availability of the medication, the duration of the regimen, and potential insurance hurdles.

“It's difficult to access…And they don't know where to get it. They may go to an emergency room, they may go to a clinic, and there's no guarantee that clinic or emergency room will even offer you post exposure prophylaxis in the United States—even though it's recommended,” Kelley said. “And then the second step of how do you get the medication? Does your insurance cover it? Do you need to enroll in a patient assistance program if your insurance doesn't cover it? There's just too many logistical hurdles.”

“The current recommended post exposure prophylaxis regimen is actually 28 days, and that's long for some people who may have had a single exposure to continue taking that medicine every single day for 28 days.”
 

Long acting injectables are a tremendous advancement, both for HIV prevention and treatment. —Colleen Kelley, MD, PhD

Although there are HIV vaccines in development, there are no FDA-approved immunizations. Kelley says the primary challenges to developing such vaccines is the structure of HIV and the ability of the virus to hide away in the body.

“The human immune system makes a very strong antibody response to the SARS-CoV-2 virus, that then helped to attenuated people who had COVID from having severe disease,” Kelley said. That same thing cannot be said of HIV. The HIV antibodies that people get neither prevent them from acquiring HIV, nor prevent them from getting severe disease. And it's because of the structure of the virus, the way that it hides from our immune system, the various ways that it integrates into our cells and just lives there silently. These are all the reasons why we've not been able to create an HIV vaccine similar to the COVID vaccine.”

Although the traditional methodology of creating vaccines has not proven to be efficacious for HIV yet, there is a much newer approach that is starting to be studied for HIV vaccines that includes broadly neutralizing antibodies (bnAbs). The International AIDS Vaccine Initiative (IAVI) has been helping to drive this area of research.

“The origin of our work on a new approach to HIV vaccine design began with the discovery, beginning in 2009, of potent broadly neutralizing antibodies (bnAbs) from large cohorts of individuals living with HIV in Africa, India, Thailand, Australia, the UK, and the US. Researchers at IAVI’s Neutralizing Antibody Center (NAC), a partnership with Scripps Research, and partners isolated and studied these bnAbs, which develop in some people after they have lived with HIV for several years. Later, researchers showed in the lab that some of these bnAbs block HIV from infecting cells,” IAVI writes on its site.

 was reported at this week’s CROI conference by ViiV Healthcare as it relates to HIV management as part of a comprehensive treatment strategy.

The ability to prevent HIV continues to evolve, but it remains to be seen if the significant strides made in HIV prevention will continue, especially in today’s governmental policy environment.




References
1. Let’s Stop HIV Together. CDC. Last reviewed February 18, 2025. Accessed March 13, 2025.
https://www.cdc.gov/stophivtogether/hiv-prevention/prep.html
2. HIV Vaccines. IAVI. Accessed March 13, 2025.
https://www.iavi.org/our-work/hiv-vaccines/

Colleen Kelley, MD, MPH, offers some insights on where we are today with the state of HIV prevention including the expanding PrEP options, why PEP is underutilized, and the challenges behind HIV vaccine development.  

HIV Prevention: Discussing PrEP, PEP, and Vaccine Development

A coalition of employers, the US Business Action to End HIV, sent a letter to Congress outlining the continued need for support from the federal government.

Why it’s Crucial to Maintain Funding for HIV Prevention, Research, Treatment 

This is the second in a series on the state of HIV today.

In late February, The US Business Action to End HIV, the largest coalition of employers dedicated to ending the HIV epidemic in the United States, sent a letter to Congress urging them to prioritize sustained federal funding for HIV prevention and treatment and underscoring the business sector’s commitment to advancing public health and ensuring progress in the fight against HIV.

“We have two goals, one to get people who are living with HIV on treatment, and two, to prevent new acquisition of HIV,” said Carl Schmid, Executive Director, HIV + Hepatitis Policy Institute.

The letter warns that funding freezes and grant delays could threaten hard-won progress, reversing declines in new HIV infections and exacerbating health disparities. Business leaders are calling on Congress to maintain investments in HIV research, prevention, and access to care, emphasizing that ending the epidemic is both a moral and economic imperative.

More specifically, the Coalition urges Congress to:

Maintain federal funding and state HIV prevention and treatment programs to safeguard decades of hard-won progress

Advance policies that sustain and expand life-saving public health efforts to keep the momentum going

Expand access to essential HIV services like testing, prevention, and treatment so everyone can stay healthy - regardless of where they live or their circumstances. (HIV continues to affect some communities more than others, particularly in parts of the US South, where access to prevention and care remains a challenge)

Strengthen public-private collaboration to close gaps in care, especially in communities most impacted by HIV.

“We saw a pretty steady decrease in the number of new HIV infections in this country between 2018 and 2022 but this progress is fragile, and reductions in funding or rollbacks and policy efforts could really risk a resurgence in new HIV infections and in preventable deaths, which would undermine all of the hard won gains that we've made,” said Stephen Massey, co-founder and co-CEO of the US Business Action to End HIV.

In terms of the business sector and their role in addressing these issues, Massey says companies have an opportunity to create a comfortable environment, to be able to have employers communicate with their employees about HIV, as well as what types of health plans they offer.

“There is an opportunity for employers to share trusted information about HIV, including how to prevent infection. There's an opportunity for employers to create workplaces where employees feel comfortable talking about HIV, asking questions, and also workplaces where employees have access to the very best care and prevention,” Massey said. “Employers play a really important role in determining health care plans that employees are offered for employees who might not be covered by their insurer. They could also provide information to employees about how they can access the social safety net of services that are available.”

“The community can advocate for ourselves, but I think it's really helpful, particularly in this time period, to have additional voices, including those of the business community,” Schmid said. “They can go into congressional offices and places where perhaps the community doesn't have the same footing.”

Sesh Sundararaman, MD, PhD

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