This is the main conclusion of a scientific literature review conducted by researchers from HypoVax Global Knowledge Hub, an international consortium that brings together immunologists, clinicians, data scientists, and public healthcare specialists dedicated to the study of vaccine hyporesponsiveness—defined as a reduced or insufficient immune response to a given vaccine.

Inequalities beyond access

Among the researchers involved is immunologist Helder Nakaya, a senior researcher at Einstein Hospital Israelita who contributed toward the identification of studies containing immunological and omics data. In a post on his LinkedIn profile, Nakaya drew attention to a structural imbalance in global scientific research: 

According to Nakaya, “we are trying to understand a problem that mainly affects poorer populations using data that come mostly from wealthier ones.” 

HypoVax Global seeks to close this gap by fostering international collaborations, generating better quality data in underrepresented regions, and providing a more accurate picture of global immunological inequalities.

Evidence compiled in an international publication

In 2024, the consortium held an international workshop about vaccine hyporesponsiveness in the Netherlands. The discussions and evidence presented were outlined in an opinion article published in November in the journal The Lancet Microbe.

In clinical trials, for example, the effectiveness of the rotavirus vaccine after 12 months ranged from 44% to 77% in high- and medium-mortality countries—all of which are low- and middle-income—while it reached 94% in low mortality countries, all of which are high-income.

Significant variations were also observed in the response to the hepatitis B vaccine. Among children under 15 years in sub-Saharan Africa, seroprotection rates varied from 85% in South Africa to 64% in the north of the continent.

Single-country comparative studies reinforced the influence of the local context. In Gabon, children from rural areas presented lower antibody responses to the influenza vaccine than those from semi-urban regions. In Uganda, adolescents from rural areas demonstrated weaker responses to various vaccines than those from urban areas.

Biological and clinical factors associated with hyporesponsiveness

The immune response to vaccines is shaped by multiple factors:

• Genetics: different ethnic groups living in the same location may present different responses and varying rates of antibody decline.
• Comorbidities: children with celiac disease exhibit lower levels of antibodies after hepatitis B vaccination and lose protection more rapidly.
• Prematurity and malnutrition: premature infants and malnourished children exhibit weaker responses to vaccines such as hepatitis B, measles, and oral poliovirus.
• Concomitant infections: nursing infants with symptomatic malaria infection present reduced responses to Hib, measles, meningococcal C, Salmonella, and tetanus vaccines.

Another important factor is the interval between doses. Schedules with longer intervals tend to induce more robust immune responses. Evidence shows that antibody levels against the acellular pertussis vaccine are significantly higher when administered at 2, 4, and 6 months, compared with accelerated schedules, such as 2, 3, and 4 months.

Pathways to reducing vaccine inequalities

According to the authors, the findings support the idea that biological and contextual conditions profoundly shape vaccine effectiveness. As a result, the rational development of new vaccines should seek strategies to modulate innate immunity, either through pre-vaccination interventions or the use of more effective adjuvants.

To make this possible, it is essential to expand the availability of diverse databases, with more inclusion of specialists and populations from low- and middle-income countries—precisely where vaccine hyporesponsiveness is most prevalent.

Artificial Intelligence tools and advanced data integration techniques are highlighted as resources with transformative potential for identifying predictive biomarkers, optimizing vaccine formulations, and generating actionable evidence tailored to the specific challenges of each population.

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The meeting addressed the state of preparedness for a next pandemic, learnings from the COVID-19 pandemic, and the viability and progress of the “100 Days Mission” launched by the UK government during the G7 in 2021. 

The most sobering learnings from the last pandemic was that 1.6 million people died before vaccines were available. Cases in an outbreak with human-to-human transmission spread logarithmically. 

Modelling data showed that 800 million infections and 8 million deaths could have been avoid in the COVID pandemic if vaccines would have been available within 100 days of availability of genome sequence. 

It’s an ambitious but possible goal

The “100 Days Mission” which has been endorsed by the G7 and G20 nations aims to have a vaccine developed, tested and emergency use authorized within those 100 days.

This is a moonshot goal as development time for a vaccine takes typically about 5-10 years, or even 25 years as for the first malaria vaccine. Are the 100 days achievable? 

If a new disease were from the Paramyxovirus or Orthopoxvirus family (or “disease X”) where we do not even know what it is, the world is not ready. 

The success of the 100 Days Mission is  based on 5 critical pillars all of which have to be established in a pre-pandemic period: 

1. Creating libraries of vaccine prototypes and platforms:

The unprecedented success of the COVID-19 vaccine availability within 326 days was only possible because of prior scientific work on other coronavirus family members such MERS and SARS-CoV1. 

Identifying pathogen families with pandemic potential, selecting one prototype within the family and then initiating R&D and platform selection work will be critical for a jump start in a next pandemic. This concept was  also embraced by WHO by moving away from the previous Blueprint list of a dozen pathogens to a family library approach. 

2. Establishing a global surveillance systems:

Early detection of pathogens with pandemic potential in the environment such as in wastewater even before an outbreak occurs is critical to avoid the evolution to outbreak to pandemic.  

Unfortunately many governments did not even build or  scale back their surveillance efforts.  

There is also reluctance by some countries to share epidemiological and genetic data for geopolitical and stigmatization reasons, but mainly because of lack of benefit back from recipient HICs. 

This is still one of the pending issues being addressed in the global Pandemic Agreement currently in late stage consultation with WHO member states.  

3. Global clinical trial and laboratory networks:

They need to be established and qualified in interpandemic time to ensure immediate readiness in an outbreak.

Lack of qualified trial sites, immunology laboratories in many low and middle income countries was one of the issues in the last pandemic and was aggravated by a complete breakdown of supply logistics. 

Initiatives such as the Bill and Melinda Gates Foundation clinical trial readiness during which 21 sites in Latin America were qualified within 4 months serve as example that these tasks are feasible. 

However, both trial sites and labs need to be kept “warm” outside of a pandemic through a constant flow of trials to not loose capabilities and ensure pandemic readiness.

4. Regionalizing vaccine manufacturing:

It would be a global game changer for access. Various initiatives to establish manufacturing capacity in Africa are underway by consortia of philantrophy but also by private industry such as the mRNA company Biontech which is establishing a modular facility in Rwanda. 

Again, like with labs and clinical sites, those new manufacturing sites need to be kept warm through constant workflow.

5. Identification of immunological markers of protection:

This measure would be important to be able to license vaccines based on immunological rather than clinical efficacy data.

Global collaboration, trust, agility, risk taking and above all equity is what scientist need to embrace to be better prepared for the next pandemic. A threat to anyone of us is a threat to all of us. And thus, failure of the “100 Days Mission”is not an option.

Opinion articles do not necessarily reflect the views of Science Arena or Hospital Israelita Albert Einstein.

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The winner is chosen by a council of more than 600 scientists from all over the world, including Nobel and Abel prize winners.

The honor, awarded to early-career scientists, was given to Fabiana Corsi Zuelli for her studies on the relationship between inflammatory changes and environmental factors in the development of first psychotic episodes.

Zuelli spent her entire academic career in the public system. “I faced the barriers of a shortage of physical and personal resources, but with the desire to experience a quality public higher education.”

In 2009, she passed the entrance exam to study a degree at USP’s Ribeirão Preto School of Nursing. In her first year, she received a research grant from the Brazilian National Council for Scientific and Technological Development (CNPQ).

She also participated in Science without Borders, a government program that operated from 2011 to 2017, giving Brazilian university students foreign exchange opportunities. While still an undergraduate, Zuelli visited the UK, where she took part in research into the impact of stress on the development of mental disorders.

Her time in the UK helped broaden her horizons in research. It also paved the way for the Brazilian to study abroad once more during postgraduate studies at the Ribeirão Preto School of Medicine.

As part of her master’s degree in neuroscience, which she completed in 2019, she spent a sandwich period at King’s College London. She then began a PhD (also in neuroscience) with a grant for a sandwich period at the University of Birmingham, UK. She defended her thesis in 2024, with funding from the São Paulo State Research Foundation (FAPESP).

In her research, Zuelli seeks to integrate two fields of health sciences: psychiatry and immunology. Her motivation, she says, is based on personal experience.

“My late aunt was diagnosed with schizophrenia. I experienced first-hand the suffering caused by this debilitating disorder, which also impacts the lives of those caring for patients. My aunt was taken care of by my mother,” says Zuelli.

For almost ten years, Zuelli dedicated herself to investigating immunological changes and environmental factors in the development of psychosis.

Her work was part of a thematic project (with funding from FAPESP, CNPQ, and the Center for Research in Inflammatory Diseases) and an international consortium known as The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions.

Inflammation and behavior

In her investigations in Ribeirão Preto, located in the interior of São Paulo state, Zuelli and her research team identified 588 cases of psychosis between 2012 and 2015. They collected blood samples for analysis from 166 patients.

“We observed that people experiencing their first psychotic episode had higher concentrations of inflammatory proteins, such as cytokines, in their blood than other individuals in the community,” explains Zuelli.

The research also found that people who suffered childhood abuse may be more susceptible to these inflammatory changes. “Individuals who experienced childhood trauma were more likely to develop diseases with inflammatory causes.”

According to Zuelli, individuals with inflammatory changes were also more vulnerable to the negative effects of daily consumption of marijuana (Cannabis sativa).

“The inflammatory state detected in some of these individuals was associated with exacerbation of the symptoms of the disease and a reduction of the brain structures involved in social and cognitive processes,” explains Zuelli.

One of the merits of the research, she highlights, is its interdisciplinary nature. “For a long time, mental disorders were considered ‘problems’ exclusive to the brain,” she says.

“Today, however, we know that there is an important connection between the brain and the rest of the body, and our results support this by showing that organic changes—inflammation detected in the blood—can influence behavior.”

Identifying inflammatory markers could pave the way for personalized treatments, says Zuelli.

During her sandwich PhD in the UK, she took part in the first clinical trial testing an adjuvant therapy for antipsychotics with a drug that modulates the immune system response, specifically in psychosis patients with inflammatory changes in the blood.

“This is an excellent example of precision medicine, in which therapy is targeted according to the individual’s biological characteristics.”

International recognition

Zuelli has received several international awards over the course of her career, including recognition from entities such as the Schizophrenia International Research Society and the World Federation of Societies of Biological Psychiatry.

At the end of January, she will travel to the University of Oxford, UK, where she will begin postdoctoral research.

“I will continue studying mechanisms related to inflammatory and metabolic changes caused by mental disorders, in order to design new stratified clinical trials,” says Zuelli.

“I believe that in the coming years, the field of immunopsychiatry will move towards increasingly personalized interventions, tailored to individual characteristics, allowing for more effective treatments aligned with the specific needs of each patient.”

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