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Vaxxers : the inside story of the Oxford AstraZeneca vaccine and the race against the virus
This is the story of a race - not against other vaccines or other scientists, but against a deadly and devastating virus. On 1 January 2020, Sarah Gilbert, Professor of Vaccinology at Oxford University, read an article about four people in China with a strange pneumonia. Within two weeks, she and her team had designed a vaccine against a pathogen that no one had ever seen before. Less than 12 months later, vaccination was rolled out across the world to save millions of lives from Covid-19. In Vaxxers, we hear directly from Professor Gilbert and her colleague Dr Catherine Green as they reveal the inside story of making the Oxford AstraZeneca vaccine and the cutting-edge science and sheer hard work behind it. This is their story of fighting a pandemic as ordinary people in extraordinary circumstances. Sarah and Cath share the heart-stopping moments in the eye of the storm; they separate fact from fiction; they explain how they made a highly effective vaccine in record time with the eyes of the world watching; and they give us hope for the future. Vaxxers invites us into the lab to find out how science will save us from this pandemic, and how we can prepare for the inevitable next one.
Book
Priorities for rapid and cost-effective vaccines to improve outbreak responses
The use of vaccine platform technologies greatly reduces the time and money required to develop a novel vaccine against an infectious disease, but much work is still needed if vaccines are to protect the world from the next pandemic.
Journal Article
Clinical development of Modified Vaccinia virus Ankara vaccines
•MVA has been used as a vaccine vector in many clinical trials.•The vaccines are well tolerated in clinical studies.•MVA has been tested in several ‘prime-boost’ regimens with high immunogenicity.•Both humoral and cell-mediated responses have been induced by vaccination.•Efficacy has been demonstrated in some studies.
The smallpox vaccine Vaccinia was successfully used to eradicate smallpox, but although very effective, it was a very reactogenic vaccine and responsible for the deaths of one or two people per million vaccinated. Modified Vaccinia virus Ankara (MVA) is a replication-deficient and attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. Many clinical trials of these new vaccines have been conducted, and the findings of these trials are reviewed here. The safety of MVA is now well documented, immunogenicity is influenced by the dose and vaccination regimen, and information on the efficacy of MVA-vectored vaccines is now beginning to accumulate.
Journal Article
Studying Reddit: A Systematic Overview of Disciplines, Approaches, Methods, and Ethics
This article offers a systematic analysis of 727 manuscripts that used Reddit as a data source, published between 2010 and 2020. Our analysis reveals the increasing growth in use of Reddit as a data source, the range of disciplines this research is occurring in, how researchers are getting access to Reddit data, the characteristics of the datasets researchers are using, the subreddits and topics being studied, the kinds of analysis and methods researchers are engaging in, and the emerging ethical questions of research in this space. We discuss how researchers need to consider the impact of Reddit’s algorithms, affordances, and generalizability of the scientific knowledge produced using Reddit data, as well as the potential ethical dimensions of research that draws data from subreddits with potentially sensitive populations.
Journal Article
A Novel Chimpanzee Adenovirus Vector with Low Human Seroprevalence: Improved Systems for Vector Derivation and Comparative Immunogenicity
Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less exposed in order to circumvent pre-existing anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1:200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.
Journal Article
Recombinant protein vaccines against SARS-CoV-2
Paul Goepfert and colleagues1 describe clinical studies of CoV2 preS dTM, a stabilised pre-fusion spike protein vaccine produced in a baculovirus expression system administered alone or with one of two oil-in-water adjuvants (AS03 or AF03), in younger or older adults (299 aged 18–49 years and 142 aged ≥50 years). Keith Chappell and colleagues2 also report a first-in-human trial of a recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]) vaccine, produced in Chinese hamster ovary cells. The vaccine was well tolerated in the young adult population, with induction of neutralising antibodies that were similar to amounts measured in recovered individuals after mild to moderate SARS-CoV-2 infection.
Journal Article
ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019
1
,
2
and is responsible for the coronavirus disease 2019 (COVID-19) pandemic
3
. Vaccines are an essential countermeasure and are urgently needed to control the pandemic
4
. Here we show that the adenovirus-vector-based vaccine ChAdOx1 nCoV-19, which encodes the spike protein of SARS-CoV-2, is immunogenic in mice and elicites a robust humoral and cell-mediated response. This response was predominantly mediated by type-1 T helper cells, as demonstrated by the profiling of the IgG subclass and the expression of cytokines. Vaccination with ChAdOx1 nCoV-19 (using either a prime-only or a prime–boost regimen) induced a balanced humoral and cellular immune response of type-1 and type-2 T helper cells in rhesus macaques. We observed a significantly reduced viral load in the bronchoalveolar lavage fluid and lower respiratory tract tissue of vaccinated rhesus macaques that were challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated SARS-CoV-2-infected animals. However, there was no difference in nasal shedding between vaccinated and control SARS-CoV-2-infected macaques. Notably, we found no evidence of immune-enhanced disease after viral challenge in vaccinated SARS-CoV-2-infected animals. The safety, immunogenicity and efficacy profiles of ChAdOx1 nCoV-19 against symptomatic PCR-positive COVID-19 disease will now be assessed in randomized controlled clinical trials in humans.
The ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 induces an immune response in rhesus macaques and leads to reduced SARS-CoV-2 viral loads in respiratory tissues and an absence of pneumonia, but not to a reduction in nasal virus shedding, compared with unvaccinated animals.
Journal Article
Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice
Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1
+
CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.
Heterologous vaccination regimens for COVID-19 could be useful for example if there is a shortage of one vaccine type. Here, Spencer
et al
. show that heterologous vaccination with a self-amplifying RNA vaccine and an adenoviral vectored vaccine performs at least as well as the homologous vaccinations in mice.
Journal Article
T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed
1
. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses
2
and might reduce the potential for disease enhancement
3
. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection
4
. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs.
5
,
6
). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)
7
given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18–55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4
+
T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8
+
T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.
A single dose of the ChAdOx1 nCoV-19 vaccine elicits antibodies and cytokine-producing T cells that might help control or prevent SARS-CoV-2 infection.
Journal Article
Enhancing protective immunity to malaria with a highly immunogenic virus-like particle vaccine
The leading malaria vaccine in development is the circumsporozoite protein (CSP)-based particle vaccine, RTS,S, which targets the pre-erythrocytic stage of
Plasmodium falciparum
infection. It induces modest levels of protective efficacy, thought to be mediated primarily by CSP-specific antibodies. We aimed to enhance vaccine efficacy by generating a more immunogenic CSP-based particle vaccine and therefore developed a next-generation RTS,S-like vaccine, called R21. The major improvement is that in contrast to RTS,S, R21 particles are formed from a single CSP-hepatitis B surface antigen (HBsAg) fusion protein, and this leads to a vaccine composed of a much higher proportion of CSP than in RTS,S. We demonstrate that in BALB/c mice R21 is immunogenic at very low doses and when administered with the adjuvants Abisco-100 and Matrix-M it elicits sterile protection against transgenic sporozoite challenge. Concurrent induction of potent cellular and humoral immune responses was also achieved by combining R21 with TRAP-based viral vectors and protective efficacy was significantly enhanced. In addition, in contrast to RTS,S, only a minimal antibody response to the HBsAg carrier was induced. These studies identify an anti-sporozoite vaccine component that may improve upon the current leading malaria vaccine RTS,S. R21 is now under evaluation in Phase 1/2a clinical trials.
Journal Article