Tag: vaccines

Why The Malaria Vaccine Quickly Loses its Effectiveness

Image source: Ekamalev at Unsplash

More than 600 000 people worldwide still die from malaria every year, according to the WHO. The vast majority of fatal cases of malaria are caused by the single-celled pathogen Plasmodium falciparum, which so far has only one approved vaccine against it, and its efficacy, which is already rather low, is also short-lived. A new study in Science Immunology may have the explanation: a lack of cross-reactivity in T helper cells.

The vaccine targets CSP, the quantitatively dominant protein on the surface of the “sporozoites”. Sporozoites are the stage of the malaria pathogen which is transmitted with the bite of the mosquito and enters human blood. “To improve the vaccine, we need to understand which protective antibodies are induced by the immunisation. But the production of such antibodies depends to a large extent on help from the so-called follicular T helper cells,” explained Dr Hedda Wardemann, immunologist and senior author of the study. “They ensure that B cells transform into antibody-producing plasma cells and memory B cells.”

To study the T helper cell response against CSP in detail, Dr Wardemann’s team examined the blood of volunteers infected with killed P. falciparum sporozoites from the vaccine strain. The volunteers were of European descent and had no prior contact with malaria pathogens. The researchers analysed the induced Plasmodium-specific follicular T helper cells at the single cell level. They focused on which sequences of CSP are recognised by the T helper cells’ receptors.

The analyses revealed that the T-cell receptors mainly targeted amino acids 311 to 333 of the CSP. But the researchers were stunned by another finding: there was virtually no cross-reactivity between the individual T-cell clones. “The receptors highly specifically bind only the CSP epitopes of the vaccine strain used. Even deviations of only a single amino acid component were not tolerated in some cases,” Dr Wardemann explained.

The immunologist points out that in the natural population of P. falciparum, sequence polymorphisms occur to a high degree in this region of the CSP. “The specificity of the T-cell clones prevents the constantly recurring natural infections with the pathogen from acting as a natural ‘booster.’ This could possibly explain why the protective effect of the malaria vaccine wears off so quickly,” Dr Wardemann said. The researcher recommends that further development of the vaccine should test whether inducing a broader spectrum of T helper cells could generate longer-lasting immune protection.

Source: German Cancer Research Centre

A Crystal Clear Look at Rabies Opens up New Vaccines

Scientists from La Jolla Institute for Immunology and the Institut Pasteur have shed light on the structure of the rabies virus glycoprotein, seen here. Credit: Heather Callaway, Ph.D., LJI

In a new study, researchers from La Jolla Institute have unveiled one of the first high-resolution looks at the rabies virus glycoprotein in its vulnerable ‘trimeric’ form. These new images, published in Science Advances, may open up a new vaccine for the deadly virus.

The CDC estimates that 59 000 people die from rabies virus every year, with 40% of those bitten by rabid animals being under 15. Some victims, especially kids, don’t realise they’ve been exposed until it is too late. The intense rabies treatment regimen is not widely available and the average $3800 is out of the reach of less well-off families.

Rabies vaccines, rather than treatments, are much more affordable and easier to administer. But according to Professor Erica Ollmann Saphire, PhD, of the La Jolla Institute, lead researcher of the new study, those vaccines also come with a massive downside.

“Rabies vaccines don’t provide lifelong protection. You have to get your pets boosted every year to three years,” she said. “Right now, rabies vaccines for humans and domestic animals are made from killed virus. But this inactivation process can cause the molecules to become misshapen – so these vaccines aren’t showing the right form to the immune system. If we made a better shaped, better structured vaccine, would immunity last longer?”

“The rabies glycoprotein is the only protein that rabies expresses on its surface, which means it is going to be the major target of neutralising antibodies during an infection,” said LJI Postdoctoral Fellow Heather Callaway, PhD, the study’s first author.

“Rabies is the most lethal virus we know. It is so much a part of our history – we’ve lived with its spectre for hundreds of years,” added Prof Saphire. “Yet scientists have never observed the organisation of its surface molecule. It is important to understand that structure to make more effective vaccines and treatments – and to understand how rabies and other viruses like it enter cells.”

Shapeshifting Rabies virus evades antibodies

Why rabies vaccines don’t provide long-term protection is still unclear, but they do know that its shape-shifting proteins are a problem.

The rabies glycoprotein has sequences that unfold and flip upward when needed, like a Swiss Army knife. The glycoprotein can shift back and forth between pre-fusion (before fusing with a host cell) and post-fusion forms. It can also come apart, changing from a trimer structure (where three copies come together in a bundle) to a monomer (one copy by itself).

This shapeshifting can make rabies invisible to human antibodies, which are built to recognise a single site on a protein. They cannot follow along when a protein transforms to hide or move those sites.

The new study gives scientists a critical picture of the correct glycoprotein form to target for antibody protection.

Capturing the glycoprotein at last

Over the course of three years, Callaway worked to stabilise and freeze the rabies glycoprotein in its pre-fusion form.

Callaway paired the glycoprotein with a human antibody, which helped her pinpoint one site where the viral structure is vulnerable to antibody attacks. The researchers then captured a 3D image of the glycoprotein using cutting-edge cryo-electron microscope equipment at LJI. 

The new 3D structure highlights several key features researchers hadn’t seen before. Importantly, the structure shows the fusion peptides, the way they appear in real life. These two important sequences link the bottom of the glycoprotein to the viral membrane, but project into the target cell during infection. Getting stable image of these sequences is challenging: other rabies researchers have had to cut them off to try to get images of the glycoprotein.

Dr Callaway solved this problem by capturing the rabies glycoprotein in detergent molecules. “That let us see how the fusion sequences are attached before they snap upward during infection,” said Prof Saphire.

Now that scientists have a clear view of this viral structure, they can better design vaccines to create antibodies with a better picture of the targt.

“Instead of being exposed to four-plus different protein shapes, your immune system should really just see one – the right one,” said Dr Callaway. “This could lead to a better vaccine.”

Preventing a family of viruses

More images are needed of rabies virus and its relatives together with neutralising antibodies, and could reveal common antibody targets for lyssaviruses, which can also infect humans and animals. According to Dr Callaway, scientists are working on solving several of these structures, which could reveal antibody targets that lyssaviruses have in common.

“Because we didn’t have these structures of the rabies virus in this conformational state before, it’s been hard to design a broad-spectrum vaccine,” Dr Callaway said.

Source: La Jolla Institute for Immunology

New Vaccines Could Focus on T Cell Response – Without Antibodies

T cell
Scanning Electron Micrograph image of a human T cell. Credit: NIH/NIAID

In a groundbreaking new study, scientists report training T cells to protect against SARS-CoV-2 even without an antibody response. This could open the way to more broadly effective vaccines.

The study’s findings appear in the Proceedings of the National Academy of Sciences.

Current vaccines prompt the creation of antibodies and immune cells that recognise the spike protein. However, these vaccines were developed using the spike protein from an older variant of SARS-CoV-2, reducing their effectiveness against newer variants. Researchers have found that immune cells called T cells tend to recognise parts of SARS-CoV-2 that don’t mutate rapidly. T cells coordinate the immune system’s response and kill cells that have been infected by the SARS-CoV-2 virus.

A vaccine that prompted the body to create more T cells against SARS-CoV-2 could help prevent disease caused by a wide range of variants. To explore this approach, a research team led by Dr Marulasiddappa Suresh from the University of Wisconsin studied two experimental vaccines that included compounds to specifically provoke a strong T-cell response in mice.

The team tested the vaccines’ ability to control infection and prevent severe disease caused by an earlier strain of SARS-CoV-2 as well as by the Beta variant, which is relatively resistant to antibodies raised against earlier strains.

When the researchers vaccinated the mice either either nasally or by injection, the animals developed T cells that could recognise the early SARS-CoV-2 strain and the Beta variant. The vaccines also caused the mice to develop antibodies that could neutralise the early strain. However, they failed to create antibodies that neutralised the Beta variant.

The mice were exposed to SARS-CoV-2 around 3 to 5 months after vaccination. Compared to the controls, vaccinated mice had very low levels of virus in their lungs and were protected against severe illness, which was true of infection with the Beta variant too. This showed that the vaccine provided protection against the Beta variant despite failing to produce effective antibodies against it.

To understand which T cells were providing this protection, the researchers selectively removed different types of T cells in vaccinated mice prior to infection. When they removed CD8 (killer) T cells, vaccinated mice remained well protected against the early strain, although not against the Beta variant. When they blocked CD4 T (helper) cells, levels of both the early strain and Beta variant in the lungs and severity of disease were substantially higher than in vaccinated mice that didn’t have their T cells removed.

These results suggest important roles for CD8 and CD4 T cells in controlling SARS-CoV-2 infection. Current mRNA vaccines do produce some T cells that recognize multiple variants. This may help account for part of the observed protection against severe disease from the Omicron variant. Future vaccines might be designed to specifically enhance this T cell response.

“I see the next generation of vaccines being able to provide immunity to current and future COVID variants by stimulating both broadly-neutralising antibodies and T cell immunity,” Dr Suresh predicted.

Source: National Institutes of Health

Aspen to Locally Produce COVID Vaccine ‘Aspenovax’ for the African Continent

Syringe withdrawing from vaccine vial
Photo by Mufid Majnun

In a news release, pharma giant Aspen has announced that it has concluded an agreement with Johnson & Johnson to manufacture an Aspen-branded COVID vaccine, Aspenovax, and to make it available throughout Africa.

This follows on from the November 2021 announcement of an agreement of terms between the two companies. This new agreement will expand the existing technical transfer and manufacturing agreements between the companies.

The agreement will grant Aspen’s South African subsidiary the rights to manufacture finished Aspenovax product from drug substance supplied by J&J. It will also make Aspenovax available to markets in Africa through transactions with designated multilateral organisations and with national governments of member states of the African Union.

Under the agreement, Aspen has secured the necessary intellectual property from Johnson & Johnson for production. There is also a good faith undertaking between the companies to expand the agreement to cover any new versions of the drug substance, such as those developed for new variants or a different formulation for administration as a booster.

The agreement will last through to the end of 2026.

Commenting on this agreement, Dr Matshidiso Moeti, World Health Organization Regional Director for Africa said: “This important agreement on sharing know-how and technologies for the production of COVID vaccines is a huge leap forward towards realising our shared vision for medicines and vaccines to be manufactured on the African soil for the African people. Vaccines are our best way out of this pandemic and local production is an essential recipe for our success.”

Stephen Saad, Aspen Group Chief Executive said: “Even with all the support in the world, none of this would be possible without the competence of our teams at Gqeberha. They knew the weight of a continent’s ambitions rested on their shoulders. They persevered and succeeded in becoming a significant supplier within the Johnson & Johnson network. Aspenovax has become a reality due to the confidence placed in their abilities. They are our African heroes.”

Exercise After Vaccination Boosts Antibodies

Photo by Barbra Olsen on Pexels

Researchers have found that a 90 minute bout of mild- to moderate-intensity exercise directly after a receiving a flu or COVID vaccine may provide an extra immune boost.

In the paper, published in Brain, Behavior, and Immunity, participants who cycled on a stationary bike or took a brisk walk for an hour-and-a-half after receiving a vaccine injection produced more antibodies in the following four weeks compared to participants who sat or continued with their daily routine post-immunisation. When the researchers ran the experiment with mice and treadmills, similar results were observed.

“Our preliminary results are the first to demonstrate a specific amount of time can enhance the body’s antibody response to the Pfizer-BioNtech COVID vaccine and two vaccines for influenza,” said Kinesiology Professor Marian Kohut, lead author of the study.

The vaccine recipients would be able to benefit people who could not cope with such exercise. Nearly half of the participants in the experiment had a BMI in the overweight or obese category. During 90 minutes of exercise, they focused on maintaining a pace that kept their heart rate around 120–140 beats per minute rather than distance.

However, the exercise duration appeared to be important: the researchers also ran the experiment with just 45-minutes of exercising. The shorter workout did not increase the participants’ antibody levels. Prof Kohut said a follow-up study might test whether 60 minutes is sufficient.

As to why prolonged, mild- to moderate-intensity exercise could improve the body’s immune response, Prof Kohut said there may be multiple reasons. Exercise increases blood and lymph flow, which helps circulate immune cells. As these cells move around the body, they’re more likely to detect antigens. The mouse experiment data also suggested that interferon alpha produced during exercise helps generate virus-specific antibodies and T- cells.

“A lot more research is needed to answer the why and how,” said Prof Kohut. “There are so many changes that take place when we exercise – metabolic, biochemical, neuroendocrine, circulatory. So, there’s probably a combination of factors that contribute to the antibody response we found in our study.”

The researchers are continuing to track the antibody response in the participants six months post-immunisation and have launched another study that focuses on exercise’s effects on people who receive booster shots.

Source: Iowa State University

Ebola Vaccine Instils Lasting Antibody Response

Ebola virus (green) is shown on cell surface.
Credit: National Institutes of Allergy and Infectious Diseases, NIH

A new study has shown that the Ebola vaccine known as rVSVΔG-ZEBOV-GP instils a robust and enduring antibody response among vaccinated individuals in areas of the Democratic Republic of Congo that are experiencing outbreaks of the disease.

The study, published in PNAS, is the first to examine post–Ebola-vaccination antibody response in the DRC, a nation of nearly 90 million. Long-term analyses of the study cohort will continue, but in the meantime, the findings will help inform health officials’ approach to vaccine use for outbreak control, the researchers said.

Ebola, one of the world’s deadliest viral diseases known to infect humans, was first identified in 1976 following an outbreak near the Ebola River in then Zaire (now DRC). Since then, outbreaks have occurred intermittently in sub-Saharan Africa, including 12 outbreaks in the DRC, where the disease remains endemic.

The single-dose rVSVΔG-ZEBOV-GP vaccine was administered to more than 300 000 individuals in the DRC during outbreaks between 2018 and 2020. However, studies examining the antibody response of vaccinated Congolese populations had been lacking.

US and DRC researchers studied individuals who received the vaccine during an Ebola outbreak in the DRC’s North Kivu Province. Between August and September 2018, 608 eligible individuals were vaccinated. In an approach known as “ring vaccination”, these participants were contacts of people infected with Ebola or contacts of those contacts as well as health care and frontline workers in affected or potentially affected areas.
Blood samples were taken at the time of vaccination, 21 days later and again after six months. They found that after 21 days, 87.2% of the study participants showed an antibody response and antibody persistence was seen in 95.6% after six months.

Source: University of California, Los Angeles

Promising Zika Vaccine Protects Foetus in Animal Trial

Mosquito
Photo by Егор Камелев on Unsplash

US researchers have shown that a Zika virus vaccine candidate is effective at preventing the Zika virus passing from mother to foetus in preclinical animal studies, according to a new study published in npj Vaccines.

“The vaccine has been shown to be safe for non-pregnant humans, but of course we need to know if it is safe and effective for the people at greatest risk: pregnant women and their fetuses,” said first author In-Jeong Kim, PhD, a viral immunologist at Trudeau Institute. “Our proof-of-concept studies conducted at Trudeau and Texas Biomed show very promising results that the vaccine given before pregnancy will provide high levels of protection for mothers and babies.”

The 2015–2016 Zika outbreak in Brazil and other countries in the Americas caused a surge in miscarriages and a constellation of birth defects, called Congenital Zika Syndrome, including abnormally small heads and neuro-developmental disorders.

“It’s important to test vaccines before the next large outbreak, because there will be another,” said senior author Jean Patterson, PhD, a virologist at Texas Biomed. “Zika is part of a family of viruses known to go through cycles. These viruses tend to spread rapidly through naïve populations that have never been exposed to the virus before, then infections drop down for years because most people have been exposed. As more and more people are born, there is a new group of naïve individuals in which the virus can once again wreak havoc. We want to help break that cycle.”

The purified, inactivated Zika vaccine (ZPIV) candidate was been tested in non-pregnant animals, showing it effectively clears the virus from blood. In Phase 1 human trials, it has been shown to be safe and elicit a protective immune response.

However for ethical and safety reasons, it is not possible to test whether the vaccine protects women and their foetuses from both infection and severe malformations, so animal models are used as a substitute.

Researchers tested the vaccine in pregnant mice and marmosets, respectively. The mouse studies, led by Dr Kim and Marcia Blackman, PhD, a viral immunologist at Trudeau, showed the vaccine prevented around 80% of foetal malformations, and neutralising antibodies were detected in foetal blood samples eight days after infection.

“We were able to detect maternal antibodies in the fetus during pregnancy and the results suggest the antibodies play a critical role in protecting fetuses from Zika virus,” Dr Kim said.

Marmosets are more sensitive to Zika infection than other nonhuman primates; previous research showed foetuses were aborted within two weeks of maternal infection.

In this study, four marmosets were immunised with the ZPIV vaccine and then exposed to Zika virus after they became pregnant. Only 1 of 12 offspring tested positive for Zika virus, demonstrating more than 90% effectiveness.

“Because the animals became pregnant at different times, our study was able to show the vaccine confers protection for at least 18 months after vaccination, which is important for showing long-lasting immunity,” Dr Patterson said.

The researchers are already testing what happens when the vaccine is administered during pregnancy.

“These studies add evidence that the Zika vaccine WRAIR developed not only protects animals against Zika virus infection, but also the congenital defects that mimic what has been observed in people,” says Kayvon Modjarrad, MD, PhD, who leads the US Army Zika vaccine programme. “Together with the early phase clinical trials, we believe these data lend even more support that this vaccine platform is a viable approach for countering the persistent threat of Zika.”

Source: Texas Biomedical Research Institute

UN Urges Group B Streptococcus Vaccine to Protect Babies

Photo by William-Fortunato on Pexels

There is an urgent need for vaccines against Group B streptococcus, a major cause of preterm births, disability and infant mortality worldwide, according to a UN-backed report published on Wednesday.

Group B streptococcus (GBS) is a gram-positive bacteria that colonises the gastrointestinal and genitourinary tract. It can be transmitted in utero, is linked to around 150 000 infant deaths each year, more than half a million preterm births and significant long-term disability.

The report by the World Health Organization (WHO) and the London School of Hygiene & Tropical Medicine (LSHTM) updates 2017 estimates, and reveals that the global burden of GBS is far higher than was previously recognised.

“This new research shows that Group B strep is a major and underappreciated threat to newborn survival and wellbeing, bringing devastating impacts for so many families globally,” said Dr Phillipp Lambach, Medical Officer from WHO’s Immunization, Vaccines and Biologicals department.

The report is the first to quantify the major contribution of GBS to preterm births, and to neurological impairments such as cerebral palsy, hearing and vision loss, that can occur following infection.

Around 15% of all pregnant women worldwide, nearly 20 million annually, carry the GBS bacterium in their vagina, which can then spread to a foetus, or to newborns during labour. At present, GBS disease prevention in newborns is by administering antibiotic prophylaxis to women during labour, if the bacterium is detected during pregnancy.

However, significant health risks remain, as this intervention is unlikely to prevent most GBS-associated stillbirths, preterm births, or GBS disease that occurs later after birth.

“It is difficult to describe the breadth or depth of the grief when your child dies, or the accompanying guilt, and how it changes you, your family, and your relationships forever,” said Debbie Forwood, whose daughter Ada was stillborn after she developed a GBS infection.

Vaccine development urged
GBS burden is highest in low and middle-income countries, where screening and treatment are most challenging to implement, with regions such as sub-Saharan Africa having the highest rates of maternal GBS.
Now is the time for action, said Joy Lawn, an LSHTM Professor who contributed to the report.  While several candidate GBS vaccines are in development, none are yet available despite decades in the pipeline. The report calls for stepping up development of an effective GBS vaccine that could be administered to expectant mothers during routine pregnancy checkups.

The partners estimate more than 50 000 GBS-related deaths, and over 170 000 pre-term births, could be avoided if over 70 per cent of pregnant women were vaccinated.

Such protection could also be highly cost-effective, they added.  Net benefits from a year of maternal vaccinations could reach as high as $17 billion, accruing over several years, provided doses are affordably priced. For Ms. Forwood, this would be a bittersweet development.

“Only a GBS vaccine could have saved Ada.  When a vaccine can be widely rolled out, I will weep and scream with the unfairness that it came too late for her, and for all the other babies who are needlessly suffering and dying every year that it is delayed,” she said.

“But I will also weep with joy that in the future, many more will live, and their families will be saved from the living hell that is the death of a child.”

Source: UN News

Vaccine to Prevent Hookworm Infection Could be a ‘Gamechanger’

Photo by Bill Oxford on Unsplash

There’s been a significant breakthrough in the development of a vaccine to prevent hookworm infection – a parasite which causes serious disease in tens of millions of people globally.

Mouse trials of the vaccine candidate in mice indicate that it is more than twice as effective than current alternatives. The results were published in Vaccines.

Professor Istvan Toth from UQ’s School of Chemistry and Molecular Biology said the easy oral administration would be a gamechanger for developing countries.

“Our vaccine candidate can be orally self-administered, bypassing the need for trained medical staff, and means there’s no requirement for special storage, enabling it to reach large, isolated populations,” Professor Toth said, noting that costs can be significantly reduced.

A serious healthcare challenge
About 500 million people worldwide are infected with hookworm, which lives within the human intestine, feeding on the host’s blood, digested through a special set of enzymes.

It’s often found in regions with poor water quality, sanitation, and hygiene – greatly impacting on the physical and cognitive development of children and increasing the risk of mortality and miscarriage.

UQ’s trials in mice showed significant improvements on an alternative vaccine candidate which only achieved a 30 to 50 per cent reduction in the number of worms.

“The UQ-developed vaccine resulted in an impressive 94% worm reduction in mice,” Professor Toth said, noting that besides being easier to deliver, it “triggers a staggeringly good immune response.”

Hookworms lose their appetite
Paper co-author Dr Mariusz Skwarczynski said the hookworm’s digestion enzyme (APR 1) was the target.

“When the function of these enzymes is blocked, the parasite starves,” Dr Skwarczynski said.

“Our vaccine produces antibodies against the hookworm enzymes responsible for the digestion of blood – they simply stop being able to eat properly.”

The researchers plan to continue working on and refining the vaccine candidate in preclinical development settings, to ensure its safety and efficacy, before beginning human clinical trials.

Source: University of Queensland

Creating a Cross-protective Coronavirus Vaccine

Image by Ivan Diaz on Unsplash

Researchers have found that by targeting the core region of the spike protein receptor-binding domain, which remains structurally similar among SARS-related viruses, they can create a vaccine that offers cross-protection against SARS coronaviruses.

The COVID pandemic, caused by the β-coronavirus SARS-CoV-2, alerted the world to the seriousness of the threat posed by novel viruses. To protect against similar future outbreaks, there is an urgent need for broadly protective vaccines against SARS-related coronaviruses. In a recent study published in Journal of Experimental Medicine, a team of researchers led by Osaka University generated an immune antigen that was based on a conserved protein on the surface of SARS-related viruses. In mice immunised with this antigen, cross-neutralising antibodies against SARS-related viruses were elicited.

The coronavirus spike protein, specifically the receptor-binding domain (RBD) of spike protein that enables the virus to attach to host cells is a target for the development of neutralising antibodies, and a promising vaccine candidate. The RBD is made of two regions: the head, which is more immune-reactive and so has the most antibodies created for it, and the core. The head however changes more rapidly, while the core region is more stable amongst SARS-related viruses. Antibodies raised against this conserved core region of the RBD can therefore generate cross-protection against multiple SARS-related viruses.

As lead authors Ryo Shinnakasu and Shuhei Sakakibara explained, “The key to generating a vaccine that offers broad cross-protection among related viruses is to target a structure on the viral surface that is highly conserved. Our approach was to generate a vaccine in which the non-conserved region was masked from the immune system by the introduction of a carbohydrate molecule (or glycan) by a method known as glycan engineering. This would in turn expose the conserved core region of the RBD of spike protein.” When used to immunise mice, protective antibodies were induced that recognised the RBD core region not only of SARS-CoV-2 but also of other SARS-related viruses, such as bat SARS-like coronavirus, WIV1-CoV.

This finding is particularly promising because it demonstrates the potential for highly protective vaccines against various SARS-related viruses. As senior author Tomohiro Kurosaki warned, “Despite the existence of effective vaccines against current viruses, there is potential for the emergence of similar viruses in the future. This highlights the real need for broadly protective vaccines against SARS-related coronaviruses.”

The novel approach of vaccine design that they describe may help protect against a future global health crisis such as that experienced during the COVID pandemic.

Source: Osaka University