COVID-19 vaccine update: Oxford vaccine close to the clinic and Sanofi turns to mRNA vaccine development

Recruitment of healthy volunteers for initial evaluation of ChAdOx1 nCoV-19, a candidate non-replicating adenovirus vaccine developed at the Oxford Vaccine Centre in underway. 

The same technology platform is being used in an experimental MERS vaccine (study ongoing). 

The COVID-19 vacccine study is a placebo-controlled, single dose study (n=560, split evenly but with 10 volunteers receiving two doses), monitored over six months and with an optional 12 month follow-up. 

Sanofi Pasteur, already active in COVID-19 protein subunit vaccine development have partnered with Translate Bio, an mRNA technology company which already has 100g scale capability for clinical grade material. The companies will develop several potential candidates over the coming months. 

Oxford Vaccine Centre study page https://covid19vaccinetrial.co.uk/ accessed 27th March 2020

Sanofi and Translate Bio collaborate to develop novel mRNA vaccine candidate against COVID-19. Company press release online 27th March 2020 https://tinyurl.com/yxyymu7x

COVID-19 vaccine clinical development gets off the mark

Vaccine development has never lacked for innovation, although as a necessarily conservative industry, only a small number of evolutionary technologies have so far been exploited in large-scale “routine” childhood and adult vaccines.

This wealth of background ingenuity, along with experience gained in earlier pandemics (SARS, MERS) and the ongoing quest for better influenza vaccines, has allowed COVID-19 vaccine development to get off to a flying start, with an impressive number of candidates incorporating both established and novel technologies now under laboratory evaluation, and with a few in, or very close to, first in human studies.

A high-profile front runner is Moderna’s mRNA-1273, comprising synthetic mRNA encoding COVID-19 S (“spike”) protein, delivered in a lipid formulation which assists in getting the mRNA into cells and to ribosomes, where it’s translated into immunising protein. Dosing is now underway in healthy adults, with safety and immunogenicity read-out anticipated by mid-June next year[1]. 

However, on the 23^rd March, Moderna raised the possibility of being able to make the vaccine available to essential healthcare personnel before year end under an emergency provision.[2] 

Another mRNA player, CureVac, encouraged by early results from an mRNA rabies vaccine study, plans to enter its own COVID-19 mRNA candidate into trials by mid-year.  CureVac hopes that the vaccine might achieve useful responses at the same very low doses used in the rabies study, allowing it to meet early demand from its existing manufacturing capability. Several other mRNA vaccine candidates under development within academia and industry (from BioNTech, Arcturus, Fosun and Pfizer) are at earlier stages of preclinical development and include a nasally administered vaccine encoding highly conserved COVID-19 proteins (eTheRNA consortium) [3].

A Chinese developed non-replicating viral vector vaccine, Ad5-nCoV (CanSino Biological and the Beijing Institute of Biotechnology) will shortly enter the clinic[4]. This exploits an engineered adenovirus (the workhorse of gene therapy) to deliver DNA encoding coronavirus proteins. The technology has a track record, being the same as used in the first Ebola vaccine to receive regulatory approval.

Adenovirus-based vaccines are not without their problems, but as a relatively well-understood platform, it’s no surprise that several companies and institutes are pursuing non-replicating adenovirus candidate vaccines, including J&J, GeoVax, Altimmune, Greffex and Vaccitech. An arguably riskier route is the use of replicating viral vectors such as measles (Institute Pasteur) and horsepox viruses (Tonix Pharma).

DNA delivery does not require a living carrier, replicating or otherwise. Inovio is applying its electroporation to push COVID-19 protein encoding DNA through the skin. Zydus Cadilla is also looking at a DNA, although has not disclosed how the encoding plasmid might be delivered.

Protein subunit vaccines are well-understood, with several candidates developed in response to the SARS pandemic. Importantly, the manufacture of protein subunit vaccines is well-established and can be accomplished to high yields in in standard bacteria and yeast expression systems, although several COVID-19 candidates involve insect cell (Sanofi, ExpreS2ion) or plant-based manufacture (IBio/CC Farming).

And, in the midst of all this experimental vaccine tech, let’s not ignore the old school approaches of formalin-inactivated virus (Sinovac) and attenuated live vaccines (Codagenix/Serum Institute of India) which have proved their worth in existing viral vaccines.

Nor should we ignore the slog ahead. The correlates of protection for COVID-19, that is what should we be looking for with respect to the quality and magnitude of a neutralising antibody response, are unknown: analysis of the immune response from recovering (and infected but asymptomatic) individuals may shed much needed light.  The phenomenon of “antibody dependent enhancement” (ADE), where the virus hijacks the host antibody response to infect certain cell types has been observed in both  non-SARS human and animal coronavirus infection. Early SARS vaccine development pointed up a potential risk of severe hypersensitivity reactions in immunised animals when challenged with virus.  

Despite the pressing need to at least be able to protect those on the front line, history dictates caution[5]. A possible silver lining of the pandemic is that revolutionary approaches such as mRNA vaccination may prove their worth much earlier than would normally be the case.  Vaccine development failures, and there will be many, will, at hte very least, will add to preparedness for the next pandemic by eliminating blind alleys. 

With a fair wind, we might see limited release of a vaccine within 18 months. Until then, and with the gradual development of what will hopefully be protective natural immunity, we all need to accept that lockdown and social distancing save lives and takes some of the pressure off our healthcare systems.

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[1] Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) to Prevent SARS-CoV-2 Infection https://tinyurl.com/vnvl7wd

[2] Moderna: Virus Vaccine May Be Available to Aid Workers by Fall, Wider Provision in 12-18 Months https://tinyurl.com/s3tm6as

[3]eTheRNA Launches an International Consortium and Starts Development of Cross-strain Protective CoV-2 mRNA Vaccine for High Risk Populations https://tinyurl.com/wdmkk6d

[4] A phase I clinical trial for recombinant novel coronavirus (2019-COV) vaccine (adenoviral vector) https://tinyurl.com/vqemt6u

[5] h Don’t rush to deploy COVID-19 vaccines and drugs without sufficient safety guarantees https://tinyurl.com/swybbya

Early COVID-19 drug studies: what have we learned?

The past week has seen first results from studies of existing antiviral drugs and repurposed agents in those hospitalised with COVID-19, raising at least as many questions as answers. A combination of two antivirals (lopinavir–ritonavir: Kaletra®) used to treat HIV infection did not reduce mortality in a randomised study conducted in almost 200 severely-ill Chinese patients[1], although with a hint that earlier treatment might just be of some benefit[2].

Avigan® (avilavir/ favipiravir), an influenza drug approved in Japan and China has been reported as clearing the COVID-19 virus in four days, versus those treated with another antiviral agents. However, this was not a randomised study and involved less severely ill subjects, with benefit confined to those receiving early treatment. Although while broadly hailed as “highly effective in media reports, Avigan’s developer (Fujifilm) has been cautious in making claims around efficacy. Avigan® has been associated with severe adverse events, limiting its use as an influenza treatment.

An investigational antiviral with a similar mechanism of action, remdesivir (GS-5734; Gilead Sciences, Inc), and which is known to be active against the SARS and MERS coronaviruses is in late-stage testing in China, the US and South Korea. Anecdotal findings from a small number of severely ill patients infected while aboard a cruise ship have suggested remdesivir may have reduced reliance on ventilator support. Despite an absence of hard evidence, the drug was approved for compassionate use in the US on March 19^th. As of today (Sunday 22^nd March), Gilead was forced to temporarily limit patient access to remdesivir due to “overwhelming demand”[3].

Similarly, chloroquine, a decades old antimalarial drug, has also been approved for compassionate use on the back of anecdotal evidence, with the hope that it may also have a prophylactic effect. A related drug, hydroxychloroquine, in combination with the antibiotic azithromycin, has been reported as reducing viral burden in a small study[4]. Both drugs have been reported to be in short supply through high demand in the US, leading to problems for autoimmune disease patients dependent on the same drugs.

Actemra®, a biologic developed for rheumatoid arthritis targets the cytokine IL-6, an immune system component responsible for the “cytokine storm” observed in CAR-T therapy and apparently a contributor to the pathology of severe COVID-10 infection has been observed to be of benefit in a small and uncontrolled study in China. A similar anti-IL-6 biologic, Kevzara® (Regeneron) is moving towards Phase III studies in COVID-19 infection.

No big wins, but, and perhaps the most you can hope for from early, essentially empirical interventions and anecdote are hints and glimmers of possible ways forward. More such early and empirical, will light the way, with China, not surprisingly, ahead of the curve with over thirty medicines (including traditional Chinese medicines) identified as having an anti-COVID-19 effect in the laboratory.

[In case you missed it in my Favourites sidebar, check out Derek Lowe's blog: 
https://blogs.sciencemag.org/pipeline/archives/2020/03/24/the-latest-coronavirus-clinical-trials#comment-314221]

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[1] A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. Cao B et al. NEJM

Online March 18^th 2020 March 18, 2020 DOI: 10.1056/NEJMoa2001282 https://tinyurl.com/ulpek4c

[2] Covid-19 — The Search for Effective Therapy. Baden LR et al. NEJM online March 18^th 2020 DOI: 10.1056/NEJMe2005477 https://tinyurl.com/yx6jrrxe

[3] Gilead pauses access to experimental Covid-19 drug due to ‘overwhelming demand’. Herper M. STAT online March 22^nd 2020 https://tinyurl.com/tum92s6

[4] Information for Clinicians on Therapeutic Options for COVID-19 Patients. CDC website accessed 22^nd March 2020. https://tinyurl.com/rx7ujpz

Life During Wartime

As you may have noticed, there’s a lot happening on this small planet of ours. One small personal bright spot is that, having spent years involved in infectious disease, from diagnostic test design through vaccine and drug development, I’ve been able to help family, friends and colleagues make sense of the pandemic and have been fortunate to engage with those whose knowledge and experience goes well beyond mine.

Let’s start with the good news. While in no way underplaying the threat posed by COVID-19, the biopharma industry has been quick off the mark, with both well-trodden and new paths to treatment and prevention under very active exploration. Experience gained from past SARS and MERS epidemics (and seasonal influenza) mean that industry and public health and regulatory agencies are not starting from scratch.

That’s not to imply that treatments and vaccines will be here a week come Tuesday. Problems encountered in early SARS vaccine studies are a reminder of just how steep the learning curve might prove to be, and, at the time of writing, early clinical data for studies of repurposed drugs in ameliorating the effect of COVID-19 infection is equivocal at best. But, every hint of potential benefit will assist in identify strategies with a higher probability of success.

My white coat-days are long gone, and my battle against COVID-19 is essentially confined to taking the obvious practical measures to keep family, friends and myself at low-risk for infection. Lord, how I miss the pub already….

The only small additional effort I can make is in using this (very) modestly visited blog to pull together what’s relevant and important in controlling COVID-19, with the hope that it just might assist in developing a sense of perspective for anyone interested in the how and why of the science and industry effort.

So, until the world has adjusted to the new normal, this blog will be mainly dedicated to selected COVID-19 news, with at least a once a day update. Comments and questions, all and any feedback more welcome than ever.

HPV vaccination just keeps on giving

HPV vaccination has the potential to eliminate
 cervical cancer in future generations

As a keen follower of developments in cancer immunotherapy (and occasional commentator), it’s easy to forget the quiet impact of past advances in cancer treatment and prevention which are now a routine element of healthcare.

A publication from the Giovanni Lorenzini Foundation, a not for profit health educator,”HPV Vaccination Concepts in the Reality of Today”, reminded me that, while effective therapeutic cancer vaccines remain elusive, prophylactic vaccination against human papilloma viruses (HPV) has achieved the initial public health goal of significantly reducing the risk of cervical cancer and, in time, will have a similar impact on other HPV infection related cancers, notably cancers of the head and neck.

HPV infection is not uncommon, with viral DNA being detectable in around 10% individuals (and up to 30% in some populations). Over 200 types of HPV have been identified, with 15 or so being linked to cancer. These “high risk” types have a propensity to integrate their DNA with that of host cells, resulting in the expression of two particular proteins (E6 and E7) with cancer-causing potential. HPV-related cancers are a significant burden, accounting for an estimated 4.5% of all cancers, most commonly cervical cancer, followed by head and neck cancers, anal and male and female genital cancers.

Cervical cancer development is generally slow: the first HPV vaccines were deployed just over a decade ago so the absolute reduction in cancer cases is unknown. Meta-analysis of studies in women receiving either an HPV vaccine or a placebo found that pre-cancerous changes in the cervix were present in 2 of every 10,000 vaccinated women and in 164 of every 10,000 unvaccinated women. In women aged 15 to 26 years (but not those aged 25 to 45 years) vaccination reduced the risk of cervical pre-cancerous changes associated with the highest risk HPV types from 341 to 157 per 10,000. 

Early HPV vaccines were only capable of protecting against two or four high risk HPV types associated with cervical cancer, with vaccines introduced in the last four years addressing nine HPV types to provide broader protection against a range of HPV-related cancers, particularly head and neck cancers arising from or orpharyngeal infection with HPV. 

While the overall incidence of head and neck cancers is declining in developed economies, largely due to decreasing tobacco use, the incidence of HPV-positive cancers has risen over the last two decades. Extending routine HPV vaccination to young males (a policy in place in the UK since July 2018) should eventually reverse this trend, while also further reducing the prevalence of HPV-associated genital cancers.

HPV vaccination has not been without controversy. A meta-analysis of 73,000 participants in HPV vaccine studies did not encounter any evidence to support much publicized claims that “debilitating illness” (including rapid increase in heart rate on sitting or standing up- postural orthostatic tachycardia syndrome) was a common side effect in girls. The uptake of HPV vaccination in the US is low relative to overall vaccination rates. Parental concern that vaccination would somehow encourage promiscuity has been proposed as one reason, although studies suggest that lack of knowledge about the purpose and benefits of HPV vaccination; a three dose vaccine schedule which may have resulted in missing doses, and vaccine cost are key contributors.

HPV vaccination may have benefits outside of cancer prevention. The prevalence of HPV in seminal fluid is twice as high in infertile men when compared with the general population. Laboratory studies have identified several mechanisms by which HPV can detrimentally alter sperm, with the presence of sperm-bound viral DNA being a predictive factor for early miscarriage. Vaccination has been shown to increase the rate of HPV clearance from infected semen and might contribute to higher success rates for couples undergoing assisted reproduction.

Photo credit: chinnapong/shutterstock.com

Zika virus: a whistle-stop tour

Zika virus (false colour transmission
electron microscope image)

In a recent piece on mRNA vaccines[mRNA vaccine technology: industry is getting the message] , I mentioned Zika virus development as an indication for this emerging technology. only to realise my ignorance of this high profile pathogen (shameful, since I spent my post-doc years working in a school of tropical medicine)

First stop in filling the knowledge gap was a visit to the ever-useful World Health Organisation website which features a comprehensive “Zika timeline”. First discovered in 1947 in monkeys living in a Ugandan forest (which gave its name to the virus), and shortly after in species of Aedes mosquito, epidemiological studies conducted in the 60s and 80s indicated widespread human exposure to the Zika virus in Africa and Asia, with infection largely associated with no, or only mild, symptoms.

The more sinister nature of Zika infection emerged in 2007 and 2008, with the first confirmed large scale outbreak on the Micronesian island of Yap, and evidence that infection could be sexually transmitted. Further outbreaks occurred on various Pacific Islands during 2013 and 2014 and pointed to a link between Zika infection and birth defects and with Guillain–Barré  syndrome, a rare autoimmune disease which affects the nervous system. A year later, an epidemic characterized by a skin rash bit otherwise mild symptoms was reported in north-eastern Brazil, but was not recognised as being due to Zika virus.

By October 2015, an increasing numbers of microcephaly cases (newborns with small heads, indicative of abnormal brain development) were being reported. Further Zika outbreaks occurred in several South American and Caribbean countries over the following year, with the first cases (via sexual transmission) being identified in the continental United States in 2016.

Being generally asymptomatic, the prevalence of Zika infection is not easy to quantify, but mosquito-transmitted infection has been reported in over 80 countries (with transmission ongoing in over 60 of these). Over 1.3 million people are thought to have been infected in Brazil alone during the 2015 outbreak. In common with other vector-borne diseases, the spread of Zika owes something to human mobility, although social factors, principally the inability to afford protection against mosquitoes and high population density have been identified as key drivers.

The Zika virus has several properties that contribute to its ready transmission and to its devastating effect on foetal development. The virus is highly persistent in whole blood (up to 100 days) and in the male reproductive tract, allowing sexual transmission. Zika has a preference for certain cell types that facilitate the passage of infection through the placenta; animal studies suggest that viral preference extends to neural progenitor cells essential for normal cortical development. Whether Zika infection is a direct cause of Guillain–Barré  syndrome  has not been established.

As with malaria, Zika’s vulnerability lies in its dependence on mosquito vectors: and targeted insecticide use, management of standing water and the conscientious use of bed nets and repellents can significantly reduce transmission. Like malaria, control initiatives are vulnerable to political and economic factors, including climate change-related changes in mosquito distribution and abundance. Unlike malaria, Zika has a simple lifecycle; as with other flaviviruses (including the causative agents of yellow fever and Japanese encephalitis), infection should, in theory, be preventable through vaccination.

Vaccine development efforts are almost contemporary with the Zika outbreak itself, beginning in the second half of 2015 with the genetic analysis of Brazilian Zika isolates, with the first clinical study of a Zika vaccine being reported in late 2017. Around 45 candidate vaccines have been developed through academic, governmental and industrial efforts, with nine of these reaching the clinic, representing both established (inactivated virus) and experimental approaches (DNA and mRNA vaccines). The WHO’s initial requirement is for a vaccine that can be deployed in response to outbreaks with the primary goal of preventing congenital Zika syndrome through minimizing virus carriage in the immediate population.

Early clinical studies have established that vaccination can elicit aneutralizing antibody responses, although, while an accepted hallmark of flavivirus vaccine efficacy, the importance of neutralising antibodies, and the minimum levels needed to establish protection have still to be established in the context of Zika infection. Other important unknowns include the duration of effective vaccine-induced immunity and whether the reproductive tract can be protected from infection.

              

Perversely, given the untold misery arising from Zika outbreaks around the globe, the virus’s propensity for neural progenitor cells may offer a new means of treating the most aggressive and intractable form of brain tumour, glioblastoma.

Chinese researchers have found that an experimental live attenuated Zika vaccine functions as an oncolytic virotherapy [Going viral] in an animal model of glioblastoma, specifically infecting and destroying glioma stem cells thought to be responsible for the inevitable recurrence of the tumour. Elimination was also observed using glioma stem cells isolated from individual patients.

Photo credit: Credit: NIH/NIAID

Targeting tooth decay

For now, brushing beats biopharma

in caries prevention

Back in the late 90s, I was involved in the licensing of an early-stage peptide drug aimed at preventing tooth decay by blocking the anchoring of the acid-producing (and enamel destroying) bacterium, Streptococcus mutans. As is not unusual in small biopharma, development was never progressed, but I’ve remained interested in the concept of caries prevention through pharmaceutical intervention. 

Tooth decay is an infectious disease, the principal villains being S.mutans, S.sobrinus and other acid-producing/acid-loving bad actors which outstrip other bacteria present on the tooth surface and modify the local environment to their advantage. S.mutans breaks down the sugars found in our diet and the resulting acid initiates and continues the destructon of enamel and dentine, an essential tooth mineral. Caries risk is influenced by a variety of factors, the most obvious being sugar consumption and oral hygiene habits, although the recent identification of highly virulent S.mutans strains by Swedish researchers associated with mutations in saliva proteins indicates that genetics may play a part.

As a bacterial disease, it’s not surprising that vaccination has been pursued as a possible means of caries prevention. Saliva contains secretory IgA (sIgA), a class of antibody evolved for the protection of mucosal surfaces and oral protection is theoretically possible providing effective levels of specific sIgA can be generated. Vaccination is also a low-cost and practical means of protecting large populations from an early age. 

Since the 70s, a multitude of potential vaccine targets expressed by both S.mutans and S.sobrinus have been identified and evaluated in a variety of formulations and different delivery routes (systemic, oral, intranasal), largely in animal models and a small number of volunteers studies. Despite more recently applied technical sophistication (including DNA vaccines and synthetic proteins combining several bacterial targets), development has never moved out of the transitional phase and the challenge of eliciting an effective, long-lasting antibody response remains. 

Almost as old a concept is “passive” immunisation- the use of bacteria-specific antibodies delivered in a mouth rinse or gel to sequester unwanted acid-producers. While the concept has been established in animal models and a few clinical studies, formulations based on mouse, bovine, chicken and even plant-grown antibodies have remained as curiosities. 

A recent approach combines advances in antibody generation to probe for targets actually present on living S.mutans  and S.sobrinus  and evolve corresponding antibody fragments which retain their specific binding properties. Fragments can be produced cheaply at large scale, and while successful in reducing caries in an animal model, formulation to give effective protection without frequent reapplication poses a formidable problem.

A variety of both natural and synthetic peptides with antimicrobial action have been evaluated as a means of ablating S.mutans and other acid-producers, although with mixed results. Clinical trials of a “specifically targeted antimicrobial peptide”- STAMP, designated C1652 and sponsored by a small US biotech company, C3J Therapeutics, are underway. C1652 was designed to act only on S.mutans to avoid unwanted effects on the oral microbiome. 

Interestingly, C1652 treatment appears to prevent S.mutans recolonization after treatment, although it’s too early to tell whether this useful property will be observed in human studies. A collaboration between Johnson & Johnson, a pharmaceutical and consumer healthcare giant,  and the University of Pennsylvania School of Dental Medicine is looking at the feasibility of low-cost antimicrobial peptide production in plants. 

Effective immunological or antimicrobial-based protection against decay probably remains decades away, but drug-based means of repairing the damage might be on the horizon. Researchers at the Dental Institute, Kings College London have shown that, tideglusib, a drug originally investigated as a potential Alzheimer’s disease treatment, acts upon stem cells present in dental pulp to stimulate dentine production. This process does occur naturally, but at a level too low to result in a robust repair. 

Tideglusib inhibits an enzyme, glycogen synthase kinase 3 (GSK-3), yhat normally serves as a brake on dentine production. When drug-loaded protein sponges were place in cavities formed in mouse teeth, sufficient dentine was produced to repair the tooth within six weeks. Optimised GSK-3 inhibitors could proof to be even more effective restoratives. 

In the meantime, the toothbrush, dentist and the fluoridation of drinking water remain our best defence against the ravages of S.mutans and its companions. 

Photo credit: Thegreenj, Wikipedia Creative Commons

A single shot

Each year, healthcare agencies undertake the crucial task of choosing which particular influenza virus strains will be included in vaccines to be manufactured and deployed in time for the next flu season. Selection is assisted by history and epidemiological surveillance but, as in this, the 2017-2018 flu season, mismatching of vaccine composition and the actual infecting strains greatly reduces the impact of vaccination.

That flu viruses regularly undergo changes that render vaccines ineffective has been known since the introduction of large scale flu immunization campaigns in the 1950s, leading to the World Health Organization setting up a global influenza surveillance and response system.

Seasonal flu infection is largely due to influenza Type A, and to a lesser extent, the generally less severe influenza Type B. Type C influenza strains cause only mild and sporadic infection. New “pandemic” strains, to which there is no widespread immunity, can pop up with devastating effect. The “Spanish Flu” of 1918-1919 may have caused 20-50 million deaths (more than in the Great War), while the 2009 “swine flu” pandemic may have caused more than half a million deaths.

Flu vaccines work by inducing a neutralising antibody response to haemagglutinin (HA), a protein expressed on the surface of the virus essential for infection and spread. HA can, unfortunately, undergo regular “antigenic shift”, necessitating annual adaption of seasonal flu vaccine composition to match the characteristics of the infecting strains.  

The logistical challenge of getting the right vaccine ready at the right time (a task still almost completely dependent on growing the selected virus strains in hen’s eggs), along with the need to be better able to deal with future flu pandemics, are powerful incentives to develop so-called “universal” flu vaccines, capable of inducing long-lasting or even lifelong protective immunity which is not compromised by the mutability of the HA protein. Moreover, recombinant protein vaccines would simplify large-scale manufacture and speed up vaccine availability in the face of a pandemic. 

Government and industrially funded research is pursuing a variety of routes towards a universal vaccine. A leading contender being developed by Vaccitech, an Oxford University spin-out (backed in part by Google’s venture fund), combines two highly-conserved core proteins (nuclear protein and matrix protein 1) that are naturally expressed by influenza A strains. A Phase II clinical study, which aims to eventually recruit over 2000 subjects aged over 65, is now underway, with recruitment of the initial tranche of volunteers announced earlier this month. It’s hoped that the vaccine will elicit both antibody and cellular immune responses to generate long-lasting protection.

A not dissimilar approach is being pursued by BiondVax. Various antigenic sequences (“epitopes”) present in HA, nuclear protein and matrix protein have been selected for their ability to elicit both antibody and cellular responses and knitted together in a single recombinant protein. The company hopes to initiate a Phase III study in Europe later this year, involving 7,700 subjects aged 50 years or older older, with at least half of participants being over 65 years of age.

Promising pre-clinical candidates include synthetic nanoparticles incorporating multiple copies of a conserved matrix protein developed at Georgia State University, while another Georgia group (in collaboration with Sanofi Pasteur) has used computational analysis to cherry-pick and combine different epitopes from HA proteins to induce antibodies broadly protective against one particularly important flu strain and its variants.

DNA vaccination, in which a piece of flu virus DNA is injected and then expressed as an immunising protein by the subject’s own cells, has been shown to reduce the effects of flu infection in primates. An advantage of DNA vaccination is that the “immunising” strand can encode several different conserved flu proteins to give broad protection. On the other hand, despite the wide optimism over the utility of DNA vaccination expressed during the last 25 years, only a handful of veterinary DNA vaccines have obtained regulatory approval.

"All done. See you again in five years"

While there’s no shortage of ingenuity and endeavour, a truly “universal” flu vaccine remains a good way off. Progress has so far been largely confined to influenza A viruses and the ideal universal vaccine will need to provide protection against influenza B (and ideally, pandemic strains and those of animal origin).

Science is only one barrier. As with other vaccines, large scale studies will be required to establish efficacy over conventional vaccines and safety, particularly in those at most risk from flu infection (young children and the elderly). Meaningful evaluation and deployment of a universal flu vaccine is likely outside the capacity of industry or national agencies and will require regional, if not global, co-operation and co-ordination if we are to finally attain adequate protection against “la grippe”.

Photo credit: CDC and Doug Jordan, M.A

Group B Streptococcus vaccine development: an eighty year old challenge

Group B streptococci 

Group B Streptococcus (GBS) and I go back a long way.  In the late 90s and early 2000s, I worked for several companies with ambitions to develop a GBS vaccine, only for hopes to be abandoned as an appreciation of the technical (and commercial) challenge sunk in.

GBS vaccine development has been kept alive over the last couple of decades largely by academic investigators and the odd small-cap biopharma, so it’s good to see a company the size of Pfizer getting involved, albeit with development being subsidised by the Bill and Melinda Gates Foundation.

GBS is a not uncommon resident of the guts and vaginas of healthy women, and is harmless until it turns up in the wrong place at the wrong time. Transmission of the bug to newborns can result in life-threatening, sometimes fatal, sepsis and meningitis. 

Microbiological screening, along with attention to risk factors such as preterm delivery and rupture of the protective amniotic membrane, can give a heads up as to the risk of delivering and infected infant and direct appropriate prophylactic antibiotic therapy. However, not every GBS case is prevented, even in well-resourced countries.

GBS is well-adapted for evasion of the immune system. Spreading bacteria express a variety of virulence factors which help them to set up house and deflect the unwanted attention of patrolling white cells. One of these factors, “capsular polysaccharide” (CPS) naturally elicits a generally ineffectual antibody response and was first investigated as a possible vaccine candidate during the 1930s. 

The immunogenicity of CPS can be boosted by chemically linking it to tetanus toxoid or other proteins (a strategy that works for Haemophilus Type B, Neisseria meningitidis and Streptococcus pneumoniae vaccines).  Investigational   glycoconjugate vaccines have resulted in reduced GBS carriage rates in healthy volunteers but not to the extent necessary for useful vaccination. A small scale study conducted in pregnant women had no beneficial effect on outcome. 

Over the last 15 years or so, whole genome sequencing and recombinant DNA technology have allowed researchers to identify bacterial surface proteins that might potentially protect against infection from a variety of GBS strains.   

MinerVax, a small Danish biotech which receives funding from the EU “Neostrep” project, reported positive results in a Phase I study of an all-protein vaccine,  with antibody responses in group of 240 healthy women elicited at all dosage levels. Pfizer’s candidate, which has just entered Phase I studies, is more old-school, being a conjugate vaccine designed to mimic multiple GBS serotypes. 

Any (potentially) preventable condition that causes infant death is rightly emotive, but harsh as it may seem, it’s not a certainty that GBS vaccination will actually prove to be universally cost-effective. Deployment may not make economic sense in countries where the incidence of GBS infection is low, but payback will hopefully prove substantial in countries such as South Africa, where the incidence of GBS infection is around five times higher than that of the UK. 

What’s more certain is that the technical challenge of effective GBS vaccination will be resolved well within the next 80 years. 

Image courtesy of James Archer, Medical Illustrator US Centers for Disease Control and Prevention 2013