Why We Still Need a Cytomegalovirus Vaccine, And Why It’s So Hard to Make One

This October, Moderna announced that its mRNA vaccine candidate against congenital cytomegalovirus (CMV) didn’t meet its protective efficacy endpoint. This news is disappointing, but not surprising. CMV is a formidable adversary and one of the most complex viruses we’ve ever tried to outsmart. Despite the challenges of developing a vaccine, the need remains critical.

Although CMV is ubiquitous, it rarely makes headlines but it should. It is the leading infectious cause of birth defects worldwide. In the United States, about 1 in 200 babies are born with CMV, and globally the annual prevalence ranges from 1 in 70 to 1 in 208 births. Of these, up to one in four will suffer lasting consequences of infection in utero, including hearing loss, developmental delays, seizures, or vision problems. In the U.S. alone, CMV causes around 20,000 congenital infections and thousands of permanent disabilities every year. In 2018, the associated annual healthcare cost of these infections was 6–7 billion dollars in the U.S.

Unlike Zika virus, which grabbed global attention, CMV spreads quietly through saliva, urine, and other body fluids. Most adults acquire it in their lifetime, often from toddlers who shed the virus for months after infection. For pregnant people, exposure can mean transmitting the virus to the fetus (congenital CMV), even if they’ve been infected before.

Yes, and that’s a big part of the problem. Natural infection doesn’t confer sterilizing immunity. People can be re-infected with different CMV strains or experience reactivation from latency, leading to fetal transmission even in seropositive mothers. So, the idea that “natural immunity is best” simply doesn’t hold water in this instance. We still need a vaccine that performs better than nature’s version and provides durable protection from infection with new virus strains and prevents reactivation of latent virus.

CMV belongs to the herpesvirus family, the same group as HSV, VZV, and EBV and is an absolute master of immune evasion. Once inside the body, it establishes lifelong infection (latency), reawakening when immunity dips. The virus expresses proteins that block antigen presentation, hijack key innate immune receptors (including natural killer cell receptors), and mimic cytokines to dampen immune responses. It even encodes its own fake IL-10 and important cytokine that counters inflammation.

Designing a vaccine that overcomes these tricks is like trying to train the immune system against a shapeshifter. Protection likely requires not one, but several arms of the immune response working together:

1. First, it has to generate antibodies that block infection - proteins that recognize and neutralize the virus before it can enter our cells. These antibodies target viral “entry tools” like the gB and pentamer proteins, which CMV uses as keys to slip into human cells.

2. Second, we need antibodies that do more than just block infection: Some antibodies act like flags, tagging infected cells so the immune system’s cleanup crews can find and destroy them.

3. Finally, we need T cells: the immune system’s long-term sentinels that can recognize and kill cells already infected with CMV and help keep the virus in check when it tries to reactivate later.

The challenge is that we still don’t know which combination or level of these responses actually prevents congenital infection. Even the correlates of protection remain elusive.

The first CMV vaccines date back to the 1970s, when live-attenuated strains showed partial success in transplant recipients. Later, a subunit vaccine based on the viral envelope protein gB achieved about 50% efficacy in seronegative women. That’s good by vaccine standards for a herpesvirus but not enough for licensure.

More recently, Moderna’s mRNA-1647 vaccine encoded both gB and the pentamer complex to target multiple routes of infection. Despite strong antibody and T-cell responses in early phase studies, its efficacy fell short in its phase 3 study. These results are disappointing but every trial refines our understanding of what protection looks like and helps define the next generation of design.

Another issue: what counts as “success”? Many CMV trials measure whether vaccinated people become infected at all which is often based on detecting the viral DNA in saliva or urine. But not every transient detection equates to disease or fetal transmission. The real clinical goal is preventing congenital infection and its consequences, not necessarily eliminating every trace of the virus. A vaccine that is able to cut transmission to fetuses by even 40–50% would prevent thousands of children from being born with lifelong disabilities. That’s worth pursuing, even if it doesn’t achieve sterilizing immunity.

New vaccine designs are focusing on teaching the immune system to recognize the virus more precisely. Some vaccines use improved versions of CMV key surface proteins reshaped to look exactly like the ones the virus uses to enter our cells. Others combine multiple viral targets in a single shot, aiming to trigger broader protection.

Researchers are also finding ways to make antibodies work harder not just blocking infection, but helping the immune system clean up infected cells more efficiently. And some teams are going after the stealth tactics used by the virus to evade the immune system directly, by designing vaccines that target the very proteins CMV uses to hide from our defenses or to stay dormant in the body.

Importantly, the effort isn’t limited to protecting pregnancies. CMV is also a serious threat for transplant patients, where reactivation of the virus can be deadly or cause organ rejection. A vaccine that reduces how much virus reappears during reactivation or how sick it makes people could save lives, even if it doesn’t prevent infection completely.

CMV may not make the nightly news, but its burden falls heavily and unfairly on families who least hear about it. Globally, congenital CMV is more common in low- and middle-income countries, and in communities where early infection is nearly universal and screening during pregnancy is inaccessible. Like is the case with other infectious diseases those at highest risk often have the least access to screening, early intervention, or care. Even a partially effective CMV vaccine would be a public-health milestone. It would protect babies, reduce disability, and ease suffering for families worldwide. Every incremental improvement brings us closer to that goal.

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