A guide to vaccinology: from basic principles to new developments
A Two-dose Schedule Could Make HIV Vaccines More Effective
One major reason why it has been difficult to develop an effective HIV vaccine is that the virus mutates very rapidly, allowing it to evade the antibody response generated by vaccines.
Several years ago, MIT researchers showed that administering a series of escalating doses of an HIV vaccine over a two-week period could help overcome a part of that challenge by generating larger quantities of neutralizing antibodies. However, a multidose vaccine regimen administered over a short time is not practical for mass vaccination campaigns.
In a new study, the researchers have now found that they can achieve a similar immune response with just two doses, given one week apart. The first dose, which is much smaller, prepares the immune system to respond more powerfully to the second, larger dose.
This study, which was performed by bringing together computational modeling and experiments in mice, used an HIV envelope protein as the vaccine. A single-dose version of this vaccine is now in clinical trials, and the researchers hope to establish another study group that will receive the vaccine on a two-dose schedule.
"By bringing together the physical and life sciences, we shed light on some basic immunological questions that helped develop this two-dose schedule to mimic the multiple-dose regimen," says Arup Chakraborty, the John M. Deutch Institute Professor at MIT and a member of MIT's Institute for Medical Engineering and Science and the Ragon Institute of MIT, MGH and Harvard University.
This approach may also generalize to vaccines for other diseases, Chakraborty notes.
Chakraborty and Darrell Irvine, a former MIT professor of biological engineering and materials science and engineering and member of the Koch Institute for Integrative Cancer Research, who is now a professor of immunology and microbiology at the Scripps Research Institute, are the senior authors of the study, which appears in Science Immunology. The lead authors of the paper are Sachin Bhagchandani PhD '23 and Leerang Yang PhD '24.
Neutralizing antibodies
Each year, HIV infects more than 1 million people around the world, and some of those people do not have access to antiviral drugs. An effective vaccine could prevent many of those infections. One promising vaccine now in clinical trials consists of an HIV protein called an envelope trimer, along with a nanoparticle called SMNP. The nanoparticle, developed by Irvine's lab, acts as an adjuvant that helps recruit a stronger B cell response to the vaccine.
In clinical trials, this vaccine and other experimental vaccines have been given as just one dose. However, there is growing evidence that a series of doses is more effective at generating broadly neutralizing antibodies. The seven-dose regimen, the researchers believe, works well because it mimics what happens when the body is exposed to a virus: The immune system builds up a strong response as more viral proteins, or antigens, accumulate in the body.
In the new study, the MIT team investigated how this response develops and explored whether they could achieve the same effect using a smaller number of vaccine doses.
"Giving seven doses just isn't feasible for mass vaccination," Bhagchandani says. "We wanted to identify some of the critical elements necessary for the success of this escalating dose, and to explore whether that knowledge could allow us to reduce the number of doses."
The researchers began by comparing the effects of one, two, three, four, five, six, or seven doses, all given over a 12-day period. They initially found that while three or more doses generated strong antibody responses, two doses did not. However, by tweaking the dose intervals and ratios, the researchers discovered that giving 20 percent of the vaccine in the first dose and 80 percent in a second dose, seven days later, achieved just as good a response as the seven-dose schedule.
"It was clear that understanding the mechanisms behind this phenomenon would be crucial for future clinical translation," Yang says. "Even if the ideal dosing ratio and timing may differ for humans, the underlying mechanistic principles will likely remain the same."
Using a computational model, the researchers explored what was happening in each of these dosing scenarios. This work showed that when all of the vaccine is given as one dose, most of the antigen gets chopped into fragments before it reaches the lymph nodes. Lymph nodes are where B cells become activated to target a particular antigen, within structures known as germinal centers.
When only a tiny amount of the intact antigen reaches these germinal centers, B cells can't come up with a strong response against that antigen.
However, a very small number of B cells do arise that produce antibodies targeting the intact antigen. So, giving a small amount in the first dose does not "waste" much antigen but allows some B cells and antibodies to develop. If a second, larger dose is given a week later, those antibodies bind to the antigen before it can be broken down and escort it into the lymph node. This allows more B cells to be exposed to that antigen and eventually leads to a large population of B cells that can target it.
"The early doses generate some small amounts of antibody, and that's enough to then bind to the vaccine of the later doses, protect it, and target it to the lymph node. That's how we realized that we don't need to give seven doses," Bhagchandani says. "A small initial dose will generate this antibody and then when you give the larger dose, it can again be protected because that antibody will bind to it and traffic it to the lymph node."
T-cell boost
Those antigens may stay in the germinal centers for weeks or even longer, allowing more B cells to come in and be exposed to them, making it more likely that diverse types of antibodies will develop.
The researchers also found that the two-dose schedule induces a stronger T-cell response. The first dose activates dendritic cells, which promote inflammation and T-cell activation. Then, when the second dose arrives, even more dendritic cells are stimulated, further boosting the T-cell response.
Overall, the two-dose regimen resulted in a fivefold improvement in the T-cell response and a 60-fold improvement in the antibody response, compared to a single vaccine dose.
"Reducing the 'escalating dose' strategy down to two shots makes it much more practical for clinical implementation. Further, a number of technologies are in development that could mimic the two-dose exposure in a single shot, which could become ideal for mass vaccination campaigns," Irvine says.
The researchers are now studying this vaccine strategy in a nonhuman primate model. They are also working on specialized materials that can deliver the second dose over an extended period of time, which could further enhance the immune response.
The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the National Institutes of Health, and the Ragon Institute of MIT, MGH, and Harvard.
CDPH: Stay Up To Date On Vaccines
The California Department of Public Health is encouraging all Californians to get vaccinated this season to protect themselves and loved ones from respiratory viruses.
Limiting the spread of respiratory viruses helps everyone, especially vulnerable members of our community like children, older adults and those who are immunocompromised. Respiratory infections like flu, COVID-19 and Respiratory Syncytial Virus are common during the fall and winter seasons and getting immunized against these diseases has been proven safe and effective in preventing serious illness and death in children and adults.
"It's time to start preparing for the fall and winter virus season, and that means getting immunized against flu, COVID-19 and RSV," said Tomás J. Aragón, CDPH Director and State Public Health Officer. "Taking this step means fewer sick days and more time with your loved ones. We are stronger when we are all protected against respiratory diseases."
RECOMMENDED VACCINES: Updated 2024-2025 flu and COVID-19 vaccines are recommended for everyone 6 months and older. RSV immunizations are recommended for eligible pregnant people, older adults, infants and toddlers. As always, talk to your healthcare provider about which vaccines are right for you and your family.
Flu: Everyone 6 months and older should get vaccinated against the flu annually, ideally before the end of October.
COVID-19: The updated 2024-2025 COVID-19 vaccine will be increasingly available throughout California beginning in September for everyone 6 months and older. The updated vaccine is expected to protect against circulating variants throughout the winter.
RSV: RSV most often spreads between October through March. The following groups should get immunized: Adults aged 75 and older; and adults aged 60-74 at increased risk; Pregnant people who are 32-36 weeks pregnant from September through January; Babies younger than 8 months and children ages 8-19 months who are at high risk for severe RSV.The RSV vaccine is not currently an annual vaccine, so adults who have already received a dose do not need another dose.
SCHEDULING: Flu, COVID-19 and RSV vaccines can all be administered during the same visit. Schedule a vaccine appointment by visiting MyTurn.Ca.Gov, or contacting your local pharmacy or health care provider.
COST: Flu, COVID-19, and RSV vaccines will be covered for most people through their health insurance plans, including Medi-Cal and regular health care providers. Those having difficulty obtaining vaccines can contact their health care provider or local health department for help finding a place to get immunized.
Vaccines For Children program is a federally funded program that provides vaccines at no cost to children, 18 and younger, who might not otherwise be vaccinated because of an inability to pay. Contact your doctor to learn if they are enrolled in VFC or visit MyTurn to find a location based on your eligibility.
ADDITIONAL LAYERS OF VIRUS PREVENTION: In addition to vaccines, people can follow simple actions to prevent viruses from spreading.
Stay Home When Sick: Staying home when you're sick prevents the spread of flu, COVID-19, RSV and even the common cold.
Test and Treat: Test for COVID-19 and flu if you have symptoms like fever, chills, runny nose, cough, sore throat, loss of taste or smell, stomach issues. If you test positive, contact your health care provider and ask about prescription medications, which work best when started right after symptoms begin. Learn more about treatments for both COVID-19 and flu.
Wear a High-quality Mask in Indoor Public Places: Wearing a high-quality mask N95, KN95, significantly reduces the spread of respiratory viruses, especially in crowded or poorly ventilated spaces.
Wash Hands: Wash hands throughout the day with soap and warm water for at least 20 seconds. If soap and water are not available, use a hand sanitizer with at least 60% alcohol.
Cover Coughs and Sneezes: Remember to cough or sneeze into your elbow, your arm, or a disposable tissue to help prevent the spread of viruses. Wash or sanitize your hands and dispose of your tissue after.
Ventilate Indoor Spaces: Good ventilation helps reduce the spread of viruses. If it is safe to do so, open doors and windows as much as possible to bring in fresh outdoor air. This can help keep virus particles from building up indoors.
Get more information about respiratory virus prevention by visiting CDPH's Respiratory Viruses webpage.
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What To Know About The Vaccines Available This Respiratory Virus Season
CNN —
Covid-19 levels in the United States are high and rising, flu season is approaching quickly, and RSV cases are already starting to tick up.
Forecasts from the US Centers for Disease Control and Prevention suggest that this respiratory disease season will be similar to last year's — which brought more than 20 hospitalizations for every 100,000 people in one week at its peak — and far worse than in pre-pandemic years.
There's a chance that the burden of disease could be lower, however, and vaccination rates will be a key factor in that trajectory.
Last year was the first year that the US had vaccines available to protect against all three major respiratory viruses — Covid-19, flu and RSV — but vaccine uptake was low for the season.
"Our top recommendation for protecting yourself and your loved ones from respiratory illness is to get vaccinated," CDC Director Dr. Mandy Cohen said in a statement. "Make a plan now for you and your family to get both updated flu and COVID vaccines this fall, ahead of the respiratory virus season."
Here's what to know about the vaccines available to protect yourself this season.
The CDC recommends that everyone ages 6 months and older receive a Covid-19 vaccine this season to stay up to date. The virus is continuously evolving, and newer versions of the vaccine could offer better protection against severe disease by targeting newer variants.
There are multiple options available; mRNA vaccines from Moderna and Pfizer were updated to target KP.2, one of the so-called FLiRT variants that have been dominant in the US since May. Those vaccines are for people 6 months and older. A more traditional protein vaccine from Novavax is also available, but it targets JN.1, a variant that is still circulating but less prominently than a few months ago. The Novavax vaccine is approved only for those ages 12 and up.
We don't know how effective these vaccines will be in practice. But the Covid-19 vaccines provided 54% protection against symptomatic infection last season, CDC data shows, despite new variants that cropped up.
The updated Covid-19 vaccines are available now, but ideal timing for getting the shot may differ based on individual circumstances.
"You have the most protection in the first few weeks to months after vaccination, and after that, antibodies tend to wane," Dr. Sandra Fryhofer, the American Medical Association's liaison to the CDC's independent vaccine advisory committee and a member of its Covid-19 vaccine workgroup, said on a recent podcast. "So you might want to time vaccination so antibodies will be at their peak for big events like weddings and major meetings. But understand, while you wait, you still run the risk of getting infected with Covid, and it's much safer to build up antibodies with vaccination than with infection."
CDC data from last season suggests that protection drops sharply about four months after someone receives a vaccine. For those who get the shot now, that could leave them with less protection around what has typically been the height of the respiratory virus season.
But Covid-19 is circulating at very high levels right now, so those at higher risk – including seniors or people who are immunocompromised – probably should not wait, Fryhofer said. They should get the updated dose as soon as possible, at least two months after their last dose or at least three months after a recent infection.
Others who were recently infected may want to wait up to six months to get an updated shot, epidemiologist Katelyn Jetelina recently wrote on her blog. "It doesn't hurt if you get it earlier, but some research shows that waiting allows our antibody factories to update more effectively," she wrote.
A seasonal flu vaccine is also recommended for everyone ages 6 months and older, and September and October are the optimal time for people to get their shot, according to the CDC.
Most people need only one dose of flu vaccine each year. But some children who are getting a flu vaccine for the first time should get two doses, spaced four weeks apart.
A higher-dose formulation of the flu vaccine is also available for those 65 and older.
RSV can be especially dangerous for older adults, as well as infants and young children. Vaccines are available to protect both groups.
The CDC updated its recommendations for older adults this year with clearer guidance. All adults 75 and older should get a single RSV shot, along with those 60 and older who are at increased risk from certain chronic medical conditions such as lung or heart disease or because they live in a nursing home or long-term care facility.
Unlike the flu and Covid-19 vaccines, the RSV vaccine is one-time dose. Older adults who received an RSV vaccine last year when they first became available do not need to get another one this year.
Pregnant women can receive an RSV vaccine that will protect a newborn, or antibodies can be given to an infant after birth.
It's safe to get both a Covid-19 and flu vaccine at the same time, according to the CDC, and it may be more convenient, rather than putting one shot off and getting sick in the meantime. If you're getting more than one shot at a time, it can be in the same arm, at least one inch apart, or in different arms.
The CDC says it's also acceptable to get Covid-19, flu and RSV shots at one time, for those who are eligible. There's no recommended wait time between them. However, the agency says, "people who get an RSV vaccine and a flu vaccine at the same visit might be more likely to have injection-site reactions or other common side effects after vaccination. Additional research is occurring to understand this better."
There isn't a combination vaccine available so far but it might not be too far off — Moderna recently said it plans to file in 2024 for regulatory approval for a combination Covid-19-flu vaccine.
Get CNN Health's weekly newsletterCovid-19, flu and RSV vaccines are widely available at pharmacies across the US. The federal government has a vaccine locator to help find available doses but notes that appointments and availability should be confirmed directly with the provider.
Vaccines may also be available from local health departments or physicians' offices, but probably not as readily.
For children and young infants, parents should check with their pediatrician. However, multiple challenges from last year — including age cutoffs at pharmacies and limited stock at pediatricians' offices — may persist this season.
These vaccines are covered by most insurance plans. Most people with private insurance, Medicare or Medicaid will still be able to get vaccinated at no out-of-pocket cost.
However, a federal program that last year provided free Covid-19 vaccines to adults without insurance and those whose insurance didn't cover all vaccine costs has now ended due to a lack of federal funding. For adults without insurance or those whose insurance does not cover the vaccine, getting the updated Covid-19 shot at a pharmacy could cost $201.99.
Free shots may still be available for people without insurance in some places. The CDC announced last month that it is distributing $62 million to state and local health departments to provide free Covid-19 vaccines to adults who wouldn't otherwise be able to afford them.
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