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Ebola: Study in Guinea reveals persistence of immunity five years after vaccination
05 Sep 2024 | By Inserm (Press Room) | Immunology, inflammation, infectiology and microbiology
Ebola virus disease outbreaks occur periodically in several sub-Saharan African countries. Two vaccines have already received WHO prequalification [1] against the Zaire Ebolavirus species. However, information on the long-term immune response to these vaccines remains patchy. It is necessary to consolidate knowledge on the subject to continue to develop the safest and most effective vaccination strategies possible, in both adults and children. In a new study conducted in Guinea, scientists from the Vaccine Research Institute (VRI), Inserm and the University of Paris-Est Créteil (unit 955 Mondor Institute for Biomedical Research) [2] have taken a further step in this direction. They have shown that the cellular immune response induced by three different vaccination strategies is maintained up to five years after vaccination. These results, which support current vaccination strategies against Ebola, are published in Nature Communications.
The Ebola virus causes high fevers and often fatal hemorrhages. Many countries in sub-Saharan Africa regularly face epidemic outbreaks. In West Africa, in 2014, the Ebola virus caused the largest epidemic known to date. It has since re-emerged several times in the Democratic Republic of Congo (DRC), but also in Guinea. Vaccination is now one of the most effective tools to combat the disease, and one of the major challenges for research is to continue to improve knowledge on the long-term immune response induced by currently available vaccines.
Since 2019, two vaccines have obtained prequalification from the World Health Organization (WHO) against the Zaire Ebolavirus strain: the rVSVΔG-ZEBOV-GP vaccine (Ervebo ® ), developed by Merck, and the vaccine strategy comprising the Ad26.ZEBOV (Zabdeno ® ) and MVA-BN-Filo (Mvabea ® ) vaccines from Janssen.
In 2022, the international PREVAC consortium (see final box) , comprising teams from Inserm, the NIH (National Institute of Health) and the London School of Hygiene and Tropical Medicine (LSHTM), published a study in the New England Journal of Medicine examining the safety and efficacy of three vaccination regimens:
the first vaccination schedule tested consisted of injecting one dose of the Ad26.ZEBOV vaccine followed 56 days later by one dose of MVA-BN-Filo;
the second regimen consisted of injecting one dose of rVSVΔG-ZEBOV-GP;
Finally, the third regimen began with a dose of rVSVΔG-ZEBOV-GP followed, 56 days later, by a booster with the same vaccine.
The published results showed a strong serum antibody response following vaccination 12 months after study entry. However, it was essential to obtain information on the long-term maintenance of the response and in particular on the cellular response (see box below) .
Humoral response and cellular response
Adaptive immune responses fall into two broad categories: the humoral response , based on the production of antibodies produced by B lymphocytes that recognize and neutralize the virus before it infects cells, and the cellular response , where CD8+ T lymphocytes identify and destroy already infected cells to limit the spread of the virus and where CD4+ T lymphocytes play a crucial role in helping B lymphocytes produce antibodies, thus enhancing the effectiveness of the immune response.
In this study, scientists were specifically interested in the cellular response, in the short, medium and long term (5 years) in participants following vaccination, according to three different vaccination schedules.
In December 2023, the 5-year follow-up of participants in the PREVAC clinical trial was completed, the results are currently being analyzed and will allow the assessment of long-term immunity induced by the vaccines. Scientists analyzed cellular immunity in 230 participants in Guinea, just after vaccination, one year and five years after vaccination.
"This is the first study from the PREVAC consortium to focus specifically on the cellular immune response of participants. It complements the knowledge already acquired on the humoral response at one year and provides the first follow-up results at 5 years ," emphasizes Aurélie Wiedemann, immunologist at the VRI and at the Mondor Institute for Biomedical Research (Inserm/Université Paris-Est Créteil) and first author of the study.
Using blood samples taken in Conakry, scientists were able to analyze the response of CD4+ and CD8+ T lymphocytes to vaccination. They showed the presence of anti-Ebola CD4+ T cells five years after vaccination, regardless of the vaccination schedule. The persistence of these responses is important for maintaining humoral immune memory in the event of exposure to the Ebola virus. The authors also show, in a subgroup of volunteers, a correlation between the CD4+ T cell response and the quantity of specific antibodies in the long term.
While the CD4+ T response is important for maintaining an antibody response, the presence of cytotoxic CD8+ T cells is also crucial for effective antiviral protection. A specific CD8+ T response was demonstrated in individuals vaccinated with two of the three vaccination regimens.
"These results will soon be supplemented by data on the humoral response - on the production of antibodies - from all the countries of the PREVAC consortium, on a larger number of participants. However, these results are promising and suggest that vaccination against the Ebola virus can induce lasting immunity. They also open the way to an adjustment of current vaccination strategies, by making it possible to assess, for example, the need for a long-term booster vaccination," explains Yves Lévy, director of the VRI and last author of the study.
In 2020, the team also published a study in Nature Communications on the immunity of people who survived an Ebola infection, two years after their discharge from the hospital. One of the next lines of research could be to compare the long-term immune response of these survivors with that induced by vaccination, in order to identify possible correlates of protection [3] against the infection, these being for the moment undetermined.
Thus, this new study could help identify vaccine responses that would be effective against infection, improve current vaccination strategies, and define long-term booster vaccination strategies to maintain protection for people particularly at risk such as health workers in Africa.
About PREVAC
PREVAC (Partnership for Research on Ebola Vaccinations; NCT02876328) is an international consortium conducting research in West Africa to evaluate the safety and effectiveness of Ebola vaccination.
The project is co-funded by Inserm, the National Institute of Allergy and Infectious Diseases (NIAID), the London School of Hygiene & Tropical Medicine (LSHTM) and the College of Medicine and Allied Health Sciences (Comahs), as well as support from Guinea, Liberia, Mali and Sierra Leone. On-the-ground support from the NGO Alima was also crucial in encouraging public participation in the research and monitoring volunteers. The manufacturers Merck and Janssen provided the vaccines used in the trial.
The project also received additional funding to continue monitoring volunteers over the long term (PREVAC-UP project coordinated by Inserm) via the EDCTP2 (European and Developing Countries Clinical Trials Partnership) program supported by the European Union.
...
https://presse.inserm.fr/ebola-une-...immunite-cinq-ans-apres-la-vaccination/68963/
-------------------------------
...
Abstract
Recent Ebola outbreaks underscore the importance of continuous prevention and disease control efforts. Authorized vaccines include Merck’s Ervebo (rVSV-ZEBOV) and Johnson & Johnson’s two-dose combination (Ad26.ZEBOV/MVA-BN-Filo). Here, in a five-year follow-up of the PREVAC randomized trial (NCT02876328), we report the results of the immunology ancillary study of the trial. The primary endpoint is to evaluate long-term memory T-cell responses induced by three vaccine regimens: Ad26–MVA, rVSV, and rVSV–booster. Polyfunctional EBOV-specific CD4[SUP]+[/SUP] T-cell responses increase after Ad26 priming and are further boosted by MVA, whereas minimal responses are observed in the rVSV groups, declining after one year. In-vitro expansion for eight days show sustained EBOV-specific T-cell responses for up to 60 months post-prime vaccination with both Ad26-MVA and rVSV, with no decline. Cytokine production analysis identify shared biomarkers between the Ad26-MVA and rVSV groups. In secondary endpoint, we observed an elevation of pro-inflammatory cytokines at Day 7 in the rVSV group. Finally, we establish a correlation between EBOV-specific T-cell responses and anti-EBOV IgG responses. Our findings can guide booster vaccination recommendations and help identify populations likely to benefit from revaccination.
...
Introduction
Since their discovery in 1976, Ebola viruses have posed a persistent threat to human health. The risk of a resurgence of Zaire Ebola virus disease (EVD) is high, as shown by its 2014–2016 reemergence in West Africa, resulting in over 28,000 cases and 11,325 fatalities. More recently, the 2018–2020 Ebola outbreak in the Democratic Republic of Congo (DRC) caused more than 3400 cases and 2200 deaths[SUP]1,2[/SUP]. These frequent outbreaks highlight the need for persistent prevention and disease control activities.
To date, two vaccines have been prequalified by the World Health Organization (WHO) and have received marketing authorization by the European Medicines Agency (EMA)[SUP]3[/SUP]. Merck’s Ervebo® (rVSV-ZEBOV) is a recombinant vesicular stomatitis Indiana virus expressing Zaire Ebola GP. The Johnson & Johnson two-dose combination comprises the adenovirus-based vaccine Zabdeno® (Ad26.ZEBOV), which expresses the Zaire Ebola virus glycoprotein (GP) from the Mayinga strain, and the Mvabea® boost (MVA-BN-Filo), encoding the GP from the Zaire Ebola virus (Mayinga strain), Sudan virus (Gulu strain), and Marburg virus (Musoke strain), along with the nucleoprotein from the Tai Forest virus[SUP]4[/SUP].
Both vaccines showed induction of immune responses in non-human primates (NHPs). Ad26.ZEBOV and MVA-BN-Filo two-dose immunization showed full protection in lethal challenge NHP experiments[SUP]5[/SUP]. One dose of the rVSVΔG-ZEBOV-GP vaccine induced ZEBOV-GP-specific IgG antibodies, which primarily mediate protection against lethal ZEBOV challenge[SUP]6[/SUP]. CD8[SUP]+[/SUP] T-cell responses, but not CD4[SUP]+[/SUP] T-cell responses, may play a minor role in protection[SUP]7[/SUP].
These vaccines have been tested in numerous clinical studies in European and African adults, adolescents, and children and have shown acceptable safety, tolerability, and robust immunogenicity[SUP]4,8,9,10,11,12,13,14,15,16[/SUP]. rVSVΔG-ZEBOV-GP has been shown to elicit a strong antibody response that correlates with the early activation of innate immunity, especially of monocytes and type I interferon-induced genes[SUP]17[/SUP]. This vaccine conferred high protection for the contacts and contacts of contacts of confirmed patients in a Guinean phase 3 ring vaccination study[SUP]11[/SUP]. Phase 1 and 2 trials of the Zabdeno (Ad26.ZEBOV) and Mvabea (MVA-BN-Filo) two-dose vaccine conducted in Europe, USA, and Africa demonstrated an excellent safety profile and induced robust humoral and cellular immune responses[SUP]4,9,15,18[/SUP]. These responses persisted for at least three years post-vaccination[SUP]13,19[/SUP] and have been predicted to persist for years[SUP]20[/SUP]. The sporadic nature of EVD outbreaks has limited the ability to conduct large phase 3 efficacy trials of this combination. Therefore, an immune-bridging study from non-human primates of the two-dose Ad26.ZEBOV, MVA-BN-Filo vaccine schedule, with the two vaccines administrated 57 days apart[SUP]21[/SUP], led to market authorization. However, despite the availability of authorized vaccines, correlates of protection and the exact level of responses required to maintain lasting protection[SUP]17[/SUP] are still uncertain.
The Partnership for Research on Ebola Vaccinations (PREVAC) consortium conducted a large vaccine trial in west Africa aimed to evaluate the safety and immunogenicity of three different vaccine regimens against Zaire Ebola virus disease: Ad26.ZEBOV followed by MVA-BN-Filo 56 days later (referred to as the Ad26–MVA group), rVSVΔG-ZEBOV-GP followed by a placebo 56 days later (the rVSV group), and rVSVΔG-ZEBOV-GP followed by a second dose of the same vaccine 56 days later (the rVSV–booster group)[SUP]22[/SUP]. The results showed a good safety profile and robust specific IgG responses, as assessed by the magnitude and frequency of responders persisting from 14 days up to 12 months after vaccination[SUP]23[/SUP].
Because most studies have focused on humoral responses as a proxy for the correlate of protection, information on the quality and durability of cellular immune responses triggered by these vaccines is scarce. As the current vaccines rely on viral vector platforms, there may be differences in terms of the durability of such responses. These unknowns represent roadblocks to the definition of public health policies in terms of the duration of protection and boosting of anamnestic responses to effectively control the spread of EVD outbreaks. Here, we took the opportunity of the five-year follow-up of the PREVAC participants to investigate the functionality, breadth, and magnitude of vaccine-elicited memory T-cell responses, and to longitudinally monitor these responses over a period of up to 5 years.
...
https://www.nature.com/articles/s41467-024-51453-z
Ebola: Study in Guinea reveals persistence of immunity five years after vaccination
05 Sep 2024 | By Inserm (Press Room) | Immunology, inflammation, infectiology and microbiology
Ebola virus disease outbreaks occur periodically in several sub-Saharan African countries. Two vaccines have already received WHO prequalification [1] against the Zaire Ebolavirus species. However, information on the long-term immune response to these vaccines remains patchy. It is necessary to consolidate knowledge on the subject to continue to develop the safest and most effective vaccination strategies possible, in both adults and children. In a new study conducted in Guinea, scientists from the Vaccine Research Institute (VRI), Inserm and the University of Paris-Est Créteil (unit 955 Mondor Institute for Biomedical Research) [2] have taken a further step in this direction. They have shown that the cellular immune response induced by three different vaccination strategies is maintained up to five years after vaccination. These results, which support current vaccination strategies against Ebola, are published in Nature Communications.
The Ebola virus causes high fevers and often fatal hemorrhages. Many countries in sub-Saharan Africa regularly face epidemic outbreaks. In West Africa, in 2014, the Ebola virus caused the largest epidemic known to date. It has since re-emerged several times in the Democratic Republic of Congo (DRC), but also in Guinea. Vaccination is now one of the most effective tools to combat the disease, and one of the major challenges for research is to continue to improve knowledge on the long-term immune response induced by currently available vaccines.
Since 2019, two vaccines have obtained prequalification from the World Health Organization (WHO) against the Zaire Ebolavirus strain: the rVSVΔG-ZEBOV-GP vaccine (Ervebo ® ), developed by Merck, and the vaccine strategy comprising the Ad26.ZEBOV (Zabdeno ® ) and MVA-BN-Filo (Mvabea ® ) vaccines from Janssen.
In 2022, the international PREVAC consortium (see final box) , comprising teams from Inserm, the NIH (National Institute of Health) and the London School of Hygiene and Tropical Medicine (LSHTM), published a study in the New England Journal of Medicine examining the safety and efficacy of three vaccination regimens:
the first vaccination schedule tested consisted of injecting one dose of the Ad26.ZEBOV vaccine followed 56 days later by one dose of MVA-BN-Filo;
the second regimen consisted of injecting one dose of rVSVΔG-ZEBOV-GP;
Finally, the third regimen began with a dose of rVSVΔG-ZEBOV-GP followed, 56 days later, by a booster with the same vaccine.
The published results showed a strong serum antibody response following vaccination 12 months after study entry. However, it was essential to obtain information on the long-term maintenance of the response and in particular on the cellular response (see box below) .
Humoral response and cellular response
Adaptive immune responses fall into two broad categories: the humoral response , based on the production of antibodies produced by B lymphocytes that recognize and neutralize the virus before it infects cells, and the cellular response , where CD8+ T lymphocytes identify and destroy already infected cells to limit the spread of the virus and where CD4+ T lymphocytes play a crucial role in helping B lymphocytes produce antibodies, thus enhancing the effectiveness of the immune response.
In this study, scientists were specifically interested in the cellular response, in the short, medium and long term (5 years) in participants following vaccination, according to three different vaccination schedules.
In December 2023, the 5-year follow-up of participants in the PREVAC clinical trial was completed, the results are currently being analyzed and will allow the assessment of long-term immunity induced by the vaccines. Scientists analyzed cellular immunity in 230 participants in Guinea, just after vaccination, one year and five years after vaccination.
"This is the first study from the PREVAC consortium to focus specifically on the cellular immune response of participants. It complements the knowledge already acquired on the humoral response at one year and provides the first follow-up results at 5 years ," emphasizes Aurélie Wiedemann, immunologist at the VRI and at the Mondor Institute for Biomedical Research (Inserm/Université Paris-Est Créteil) and first author of the study.
Using blood samples taken in Conakry, scientists were able to analyze the response of CD4+ and CD8+ T lymphocytes to vaccination. They showed the presence of anti-Ebola CD4+ T cells five years after vaccination, regardless of the vaccination schedule. The persistence of these responses is important for maintaining humoral immune memory in the event of exposure to the Ebola virus. The authors also show, in a subgroup of volunteers, a correlation between the CD4+ T cell response and the quantity of specific antibodies in the long term.
While the CD4+ T response is important for maintaining an antibody response, the presence of cytotoxic CD8+ T cells is also crucial for effective antiviral protection. A specific CD8+ T response was demonstrated in individuals vaccinated with two of the three vaccination regimens.
"These results will soon be supplemented by data on the humoral response - on the production of antibodies - from all the countries of the PREVAC consortium, on a larger number of participants. However, these results are promising and suggest that vaccination against the Ebola virus can induce lasting immunity. They also open the way to an adjustment of current vaccination strategies, by making it possible to assess, for example, the need for a long-term booster vaccination," explains Yves Lévy, director of the VRI and last author of the study.
In 2020, the team also published a study in Nature Communications on the immunity of people who survived an Ebola infection, two years after their discharge from the hospital. One of the next lines of research could be to compare the long-term immune response of these survivors with that induced by vaccination, in order to identify possible correlates of protection [3] against the infection, these being for the moment undetermined.
Thus, this new study could help identify vaccine responses that would be effective against infection, improve current vaccination strategies, and define long-term booster vaccination strategies to maintain protection for people particularly at risk such as health workers in Africa.
About PREVAC
PREVAC (Partnership for Research on Ebola Vaccinations; NCT02876328) is an international consortium conducting research in West Africa to evaluate the safety and effectiveness of Ebola vaccination.
The project is co-funded by Inserm, the National Institute of Allergy and Infectious Diseases (NIAID), the London School of Hygiene & Tropical Medicine (LSHTM) and the College of Medicine and Allied Health Sciences (Comahs), as well as support from Guinea, Liberia, Mali and Sierra Leone. On-the-ground support from the NGO Alima was also crucial in encouraging public participation in the research and monitoring volunteers. The manufacturers Merck and Janssen provided the vaccines used in the trial.
The project also received additional funding to continue monitoring volunteers over the long term (PREVAC-UP project coordinated by Inserm) via the EDCTP2 (European and Developing Countries Clinical Trials Partnership) program supported by the European Union.
...
https://presse.inserm.fr/ebola-une-...immunite-cinq-ans-apres-la-vaccination/68963/
-------------------------------
- Article
- Open access
- Published: 03 September 2024
- Aurélie Wiedemann,
- Edouard Lhomme,
- Mélanie Huchon,
- Emile Foucat,
- Marion Bérerd-Camara,
- Lydia Guillaumat,
- Marcel Yaradouno,
- Jacqueline Tambalou,
- Cécile Rodrigues,
- Alexandre Ribeiro,
- Abdoul Habib Béavogui,
- Christine Lacabaratz,
- Rodolphe Thiébaut,
- Laura Richert,
- Yves Lévy &
- the Prevac study team
...
Abstract
Recent Ebola outbreaks underscore the importance of continuous prevention and disease control efforts. Authorized vaccines include Merck’s Ervebo (rVSV-ZEBOV) and Johnson & Johnson’s two-dose combination (Ad26.ZEBOV/MVA-BN-Filo). Here, in a five-year follow-up of the PREVAC randomized trial (NCT02876328), we report the results of the immunology ancillary study of the trial. The primary endpoint is to evaluate long-term memory T-cell responses induced by three vaccine regimens: Ad26–MVA, rVSV, and rVSV–booster. Polyfunctional EBOV-specific CD4[SUP]+[/SUP] T-cell responses increase after Ad26 priming and are further boosted by MVA, whereas minimal responses are observed in the rVSV groups, declining after one year. In-vitro expansion for eight days show sustained EBOV-specific T-cell responses for up to 60 months post-prime vaccination with both Ad26-MVA and rVSV, with no decline. Cytokine production analysis identify shared biomarkers between the Ad26-MVA and rVSV groups. In secondary endpoint, we observed an elevation of pro-inflammatory cytokines at Day 7 in the rVSV group. Finally, we establish a correlation between EBOV-specific T-cell responses and anti-EBOV IgG responses. Our findings can guide booster vaccination recommendations and help identify populations likely to benefit from revaccination.
...
Introduction
Since their discovery in 1976, Ebola viruses have posed a persistent threat to human health. The risk of a resurgence of Zaire Ebola virus disease (EVD) is high, as shown by its 2014–2016 reemergence in West Africa, resulting in over 28,000 cases and 11,325 fatalities. More recently, the 2018–2020 Ebola outbreak in the Democratic Republic of Congo (DRC) caused more than 3400 cases and 2200 deaths[SUP]1,2[/SUP]. These frequent outbreaks highlight the need for persistent prevention and disease control activities.
To date, two vaccines have been prequalified by the World Health Organization (WHO) and have received marketing authorization by the European Medicines Agency (EMA)[SUP]3[/SUP]. Merck’s Ervebo® (rVSV-ZEBOV) is a recombinant vesicular stomatitis Indiana virus expressing Zaire Ebola GP. The Johnson & Johnson two-dose combination comprises the adenovirus-based vaccine Zabdeno® (Ad26.ZEBOV), which expresses the Zaire Ebola virus glycoprotein (GP) from the Mayinga strain, and the Mvabea® boost (MVA-BN-Filo), encoding the GP from the Zaire Ebola virus (Mayinga strain), Sudan virus (Gulu strain), and Marburg virus (Musoke strain), along with the nucleoprotein from the Tai Forest virus[SUP]4[/SUP].
Both vaccines showed induction of immune responses in non-human primates (NHPs). Ad26.ZEBOV and MVA-BN-Filo two-dose immunization showed full protection in lethal challenge NHP experiments[SUP]5[/SUP]. One dose of the rVSVΔG-ZEBOV-GP vaccine induced ZEBOV-GP-specific IgG antibodies, which primarily mediate protection against lethal ZEBOV challenge[SUP]6[/SUP]. CD8[SUP]+[/SUP] T-cell responses, but not CD4[SUP]+[/SUP] T-cell responses, may play a minor role in protection[SUP]7[/SUP].
These vaccines have been tested in numerous clinical studies in European and African adults, adolescents, and children and have shown acceptable safety, tolerability, and robust immunogenicity[SUP]4,8,9,10,11,12,13,14,15,16[/SUP]. rVSVΔG-ZEBOV-GP has been shown to elicit a strong antibody response that correlates with the early activation of innate immunity, especially of monocytes and type I interferon-induced genes[SUP]17[/SUP]. This vaccine conferred high protection for the contacts and contacts of contacts of confirmed patients in a Guinean phase 3 ring vaccination study[SUP]11[/SUP]. Phase 1 and 2 trials of the Zabdeno (Ad26.ZEBOV) and Mvabea (MVA-BN-Filo) two-dose vaccine conducted in Europe, USA, and Africa demonstrated an excellent safety profile and induced robust humoral and cellular immune responses[SUP]4,9,15,18[/SUP]. These responses persisted for at least three years post-vaccination[SUP]13,19[/SUP] and have been predicted to persist for years[SUP]20[/SUP]. The sporadic nature of EVD outbreaks has limited the ability to conduct large phase 3 efficacy trials of this combination. Therefore, an immune-bridging study from non-human primates of the two-dose Ad26.ZEBOV, MVA-BN-Filo vaccine schedule, with the two vaccines administrated 57 days apart[SUP]21[/SUP], led to market authorization. However, despite the availability of authorized vaccines, correlates of protection and the exact level of responses required to maintain lasting protection[SUP]17[/SUP] are still uncertain.
The Partnership for Research on Ebola Vaccinations (PREVAC) consortium conducted a large vaccine trial in west Africa aimed to evaluate the safety and immunogenicity of three different vaccine regimens against Zaire Ebola virus disease: Ad26.ZEBOV followed by MVA-BN-Filo 56 days later (referred to as the Ad26–MVA group), rVSVΔG-ZEBOV-GP followed by a placebo 56 days later (the rVSV group), and rVSVΔG-ZEBOV-GP followed by a second dose of the same vaccine 56 days later (the rVSV–booster group)[SUP]22[/SUP]. The results showed a good safety profile and robust specific IgG responses, as assessed by the magnitude and frequency of responders persisting from 14 days up to 12 months after vaccination[SUP]23[/SUP].
Because most studies have focused on humoral responses as a proxy for the correlate of protection, information on the quality and durability of cellular immune responses triggered by these vaccines is scarce. As the current vaccines rely on viral vector platforms, there may be differences in terms of the durability of such responses. These unknowns represent roadblocks to the definition of public health policies in terms of the duration of protection and boosting of anamnestic responses to effectively control the spread of EVD outbreaks. Here, we took the opportunity of the five-year follow-up of the PREVAC participants to investigate the functionality, breadth, and magnitude of vaccine-elicited memory T-cell responses, and to longitudinally monitor these responses over a period of up to 5 years.
...
https://www.nature.com/articles/s41467-024-51453-z