RSV stands for 𝗥𝗲𝘀𝗽𝗶𝗿𝗮𝘁𝗼𝗿𝘆 𝘀𝘆𝗻𝗰𝘆𝘁𝗶𝗮𝗹 𝘃𝗶𝗿𝘂𝘀. The World Health Organisation (WHO) has identified RSV as a global health issue. A few vaccine candidates and monoclonal antibody are in development/trials, with the aim to have an affordable means to prevent RSV.
Currently in South Africa a vector vaccine, classed as genetically modified, is drawing a lot of comment since the notice to run clinical trials was published.
𝑾𝒉𝒚 𝒅𝒐 𝒘𝒆 𝒏𝒆𝒆𝒅 𝒕𝒐 𝒕𝒂𝒓𝒈𝒆𝒕 𝑹𝑺𝑽 𝒘𝒊𝒕𝒉 𝒂 𝒗𝒂𝒄𝒄𝒊𝒏𝒆?
RSV is the leading pulmonary cause of death in the under 5 age group, for which no vaccine is available. Estimates in children under 5 years old show 33.1 million episodes of acute lower respiratory tract infection (ALRI). In the same age group, 3.2 million hospital admissions and as many as 118 200 deaths were attributable to RSV worldwide in 2015. Of these deaths, 50% occur during the first 6 months of life (neonatal deaths at 0‐28 days are frequent) and 99% occur in developing countries, like South Africa. These are thought to be under-estimation, due to lack of diagnostic testing, especially in Low-income settings.
Case Fatality Rate (CFR) estimates for 2015 in infants 0‐5 and 6‐11 months of age in developing countries were 2.2 (1.8‐2.7) and 2.4 (1.9‐3.2). A second meta‐analysis identified the highest case fatality rates in Kenya, Morocco, South Africa, and Mozambique. Data from the SARI surveillance system estimates the overall incidence of LRTI in South African children <5 years of age to be 2530-3173 per 100,000 with the highest incidence in children aged <1 year (annual range 8446-10532 per 100,000). Another South African study shows that infants with RSV-associated illness were 4.6-fold (95% CI, 2.4- to 8.6-fold) more likely to be hospitalized within 15 days of the illness than those with other respiratory illness. Many young children hospitalised for RSV (especially pre-term infants) require respiratory intervention, such as respirators and often suffer longer term consequences of RSV infection. This includes lung damage and chronic wheeze. In addition, RSV infection in infants does not result protective immune responses against future infection and often infants are re-infected. Currently, there are two products (both monoclonal antibodies) licenced to prevent RSV, which are expensive. These are generally not accessible in low income settings. Another monoclonal antibody is in clinical trials that shows promise and would have comparable cost to vaccines.
An RSV vaccine that prevents severe disease in young infants, and prevents person to person transmission is needed to reduce morbidity and mortality, particularly in the under 5 age group.
Unless clinical development stage testing shows a likely effectiveness and safety of a vaccine, it will not go into clinical trials. Once in trial phases, the vaccine would first need to be proven safe and effective in healthy adults before moving to higher risk groups such as infants. In 2015, RSV prevention and therapeutic strategies were reviewed by Mazur et al. They identified ten vaccine candidates in clinical development, and only 40% are continuing in clinical trials. By mid-2018, 19 vaccine candidates and monoclonal antibodies for different target populations were in clinical trials, and many more are in preclinical development. Four of these vaccines use a form of adenovirus. While the race is on to find a successful, safe vaccine for young infants, targeting a virus that itself does not induce long term immunity in this group, has been difficult. The proposed vaccine has made it to advanced stages of clinical testing. In addition, South African good clinical practice guidelines and laws that govern clinical trials stipulate that a vaccine cannot be tested on South African participants unless it is intended to be registered to prevent illness in South Africa.
𝑻𝒉𝒆 𝒑𝒓𝒐𝒑𝒐𝒔𝒆𝒅 𝑽𝒂𝒄𝒄𝒊𝒏𝒆: 𝑪𝒉𝑨𝒅155-𝑹𝑺𝑽
ChAd155 refers to a replication defective chimpanzee (Ch) derived adenovirus (Ad), serotype 155. This means it is a chimp virus that cannot replicate or infect humans. This virus has also been genetically modified to express RSV proteins. This means ChAd155 will “show” the RSV proteins. These are the F-protein (fusion protein responsible for RSV attachment to the host cell), N-protein (an internal nucleocapsid protein, ie: encapsulates the RNA) and M2-1 (a protein required for viral transcription). This is intended to induce both humoral and cell mediated immunity, including B- and T-cell response, neutralising antibody against F-antigen and CD8T-cells against the F-, N- and M2-1- antigens. This means that after vaccination, an infant could have longer term protective immunity against RSV infection. The ultimate goal is to administer this in children from 2 months of age alongside the normal (non-seasonal) vaccine schedule.
If most kids are immunised from a very young age, this will prevent young infants from getting sick, and also interrupt the person to person transmission. If this vaccine is licenced, it could save many South African children’s lives, particularly children in low income settings.
Simian adenoviruses are an advantage for vector-vaccines. They have low pre-existing immunity in humans (so this won’t interfere with the immune response), are highly immunogenic (so would induce higher immune protection) and can be mutated to disable replication in normal human cells. The downside is that these vaccines require a booster for high T-cell response.
This vaccine has already been tested in healthy adults (Phase 1: Jul-15 to Jul-17. NCT02491463) for safety and immunogenicity (inducing B-cell and RSV neutralising antibodies in RSV-seropositive adults). In short it is safe. Phase 2 (NCT02927873) will be tested in in RSV-seropositive infants aged 12 to 23 Months and is due for completion in 2020. It will then move to the same category of infants 6-12 months of age, and then lastly the target group: 2-6 months of age. Safety and immunogenicity in each group will be evaluated before proceeding.
Legislation treats this vaccine as a GMO (genetically modified organisms) product. This means in addition to all the checks and balances involved in pharmaceutical regulations, it requires public engagement, ERA (environmental risk assessment) and additional evaluation of the quality, safety and efficacy of the product before it can enter clinical trial or marketing phases.
Is there a chance that the GMO Simian adenovirus may create a hybrid with natural viruses?
No: The Vaccine contains “replication defective” adenovirus. It cannot replicate/create “offspring”.
Is there a chance that it will cause adenovirus infections in humans?
No: Answer is same as above, in addition this adenovirus does not infect humans.
Is there a chance that foreign RNA, especially GMO viral RNA could be incorporated into our own and cause other health concerns?
No, daily we ingest organisms that have “foreign” DNA. We have microbes that live within our bodies that have “foreign DNA”. Our own cells do not incorporate this DNA. Some RNA viruses can hijack our body’s cells to replicate their genomes. This is only done within those cells and does not change our own DNA. Again, this is a replication deficient virus, so not even this can happen.
The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates. Natalie I Mazur, Deborah Higgins, Marta C Nunes, José A Melero, Annefleur C Langedijk, Nicole Horsley, Ursula J Buchholz, Peter J Openshaw, Jason S McLellan, Janet A Englund, Asuncion Mejias, Ruth A Karron, Eric AF Simões, Ivana Knezevic, Octavio Ramilo, Pedro A Piedra, Helen Y Chu, Ann R Falsey, Harish Nair, Leyla Kragten-Tabatabaie, Anne Greenough, Eugenio Baraldi, Nikolaos G Papadopoulos, Johan Vekemans, Fernando P Polack, Mair Powell, Ashish Satav, Edward E Walsh, Renato T Stein, Barney S Graham, Louis J Bont; in collaboration with Respiratory Syncytial Virus Network (ReSViNET) Foundation, Lancet Infect Dis 2018, https://linkinghub.elsevier.com/retrieve/pii/S1473309918302925
Burden of Respiratory Syncytial Virus Infection in South African Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Pregnant and Postpartum Women: A Longitudinal Cohort Study. Shabir A Madhi Clare L Cutland Sarah Downs Stephanie Jones Nadia van Niekerk Eric A F Simoes Marta C Nunes. Clinical Infectious Diseases 2018, Volume 66, Issue 11, Pages 1658–1665, https://academic.oup.com/cid/article/66/11/1658/4749671
Respiratory syncytial virus is an “opportunistic” killer. Mauricio T. Caballero and Fernando P. Polack MD. https://onlinelibrary.wiley.com/doi/full/10.1002/ppul.23963 Pediatric Pulmonology 2018.
Vector-based genetically modified vaccines: Exploiting Jenner’s legacy. Bahar Ramezanpoura, Ingrid Haana, Ab Osterhaus, Eric Claassen. Vaccine, 2016. Volume 34, Issue 50, Pages 6436-6448. https://www.sciencedirect.com/science/article/pii/S0264410X16305102?via%3Dihub
More info on what case fatality rate means: https://www.britannica.com/science/case-fatality-rate