Further drafting of the guidance on risk assessment and risk management of LM mosquitoes

The current draft is much improved over the original, and I compliment the authors for their responses. One issue was addressed originally but seems to have persisted in the current version. This relates to production and release quality assurance as opposed to biosafety.

"Rationale
The released LM mosquitoes do not behave as expected.  Gene silencing or other production failures result in the release of non-sterile or competent mosquitoes and thus increasing the vector population."

It is quite possible that the LM mosquitoes will not behave as expected. However, it is unlikely that increasing the vector population - at least due to silencing or production failures - will cause an increase in the wild population. This is because the production must be supervised and monitored closely enough to ensure that this does not happen by measures including: (1) monitoring the phenotype that is relevant to transmission; (2) ensuring sexual sterilization protocols (if any) are rigidly adhered to and confirmed and; (3) releasing only males or, if females are released, they are released in such small numbers that no significant contribution to the wild population occurs. As for silencing occurring, it is possible that this could restore a wild-type phenotype, but it seems higly unlikely that it would result in higher fecundity or vector competence.

The document might specify such safety measures as part of the production and release process.

In contrast, it is quite possible that an increase in another vector species abundance might occur as a result of an empty niche. The invasive species of mosquito, Aedes albopictus, has displaced Aedes aegypti in the US, and it is likely that a control effort specifically against Ae. albopictus would allow the return of Aedes aegypti. This possibility should be considered on a case-by-case basis.

Some expert revision on the former version of the guidance document recommended the exclusion of text related to containment production of mosquitoes since containment measures are not covered by the Cartagena Protocol on Biosafety .

In this Quality Assurance & Biosafety thread posted by Dr. Benedict, it seems that there is a relevant link between containment production and the safety release of LM mosquitoes.

I would like to hear furhter comments and recommendations on this issue, please: is production and release quality assurance part of the risk assessment of the release into the environment of LM mosquitoes since if not applied could result in a hazard after environmental releases, and as such, should it be included in the Guidance Document?

Ms. Fontes raises a good question about which I will offer some
clarification of my thinking. I agree that part of the risk assessment
should include a comprehensive description of the intended LMO *and* the
anticipated variant forms that will be released (recombinants,
loss-of-function mutants etc.). The frequency of these should be known and
reported based on experiments and experience during production under the
specific production management plan that will be implemented.





It is important that the conditions under which the LMO is produced have
been documented to consistently produce release material containing a
reported frequency of variants so that the risk assessment can consider the
effects of all LMOs, not simply those that are normal.





I recommend that the risk assessment stop "at the door" of the production
facility,  but that it encompass the entire suite of normal forms and
variants of the product that will be released, and whose frequency and
nature is known. (This is already a part of the existing LMO description
that requires knowledge of stability.)





Novel interactions of the LMO, and deviations that might occur after release
will be informed by variants that are observed in the laboratory or
production, but will also include a more comprehensive set of potential
natural interactions.



Mark Q. Benedict

I agree with Dr. Benedict's comments about quality assurance. No release efforts should take place in the absence of rigorous Good Manufacturing Practices (GMP)at the facilites prodcuing the transgenic mosquitoes.

I also agree that it is extremely unlikely that transgenic mosquitoes will add in any extended period of time to the total number of mosquitoes in a target area. The design of the currently-favored strategies is to reduce mosquito numbers (population suppression) or change the nature of the target population for their ability to transmit pathogens (population replacement). Since both of these are engineering efforts, design criteria include aspects that prevent explosive increases in mosquito numbers.